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Integrated Exposomics/Metabolomics for Rapid Exposure and Effect Analyses
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  • Mira Flasch
    Mira Flasch
    Faculty of Chemistry, Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
    Vienna Doctoral School of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
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    Orcidhttps://orcid.org/0000-0002-3518-3885
  • Veronika Fitz
    Veronika Fitz
    Vienna Doctoral School of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria
    Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
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  • Evelyn Rampler
    Evelyn Rampler
    Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
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    Orcidhttps://orcid.org/0000-0002-9429-7663
  • Chibundu N. Ezekiel
    Chibundu N. Ezekiel
    Department of Microbiology, Babcock University, 121103 Ilishan Remo, Ogun State, Nigeria
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    Orcidhttps://orcid.org/0000-0002-2113-2948
  • Gunda Koellensperger
    Gunda Koellensperger
    Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
    Exposome Austria, Research Infrastructure and National EIRENE Hub, 1090 Vienna, Austria
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    Orcidhttps://orcid.org/0000-0002-1460-4919
  • Benedikt Warth*
    Benedikt Warth
    Faculty of Chemistry, Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
    Exposome Austria, Research Infrastructure and National EIRENE Hub, 1090 Vienna, Austria
    *Email: [email protected]. Tel: +43 1 4277 70806.
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    Orcidhttps://orcid.org/0000-0002-6104-0706
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JACS Au

Cite this: JACS Au 2022, 2, 11, 2548–2560
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https://doi.org/10.1021/jacsau.2c00433
Published November 7, 2022

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CC-BY 4.0 .

Abstract

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The totality of environmental exposures and lifestyle factors, commonly referred to as the exposome, is poorly understood. Measuring the myriad of chemicals that humans are exposed to is immensely challenging, and identifying disrupted metabolic pathways is even more complex. Here, we present a novel technological approach for the comprehensive, rapid, and integrated analysis of the endogenous human metabolome and the chemical exposome. By combining reverse-phase and hydrophilic interaction liquid chromatography (HILIC) and fast polarity-switching, molecules with highly diverse chemical structures can be analyzed in 15 min with a single analytical run as both column’s effluents are combined before analysis. Standard reference materials and authentic standards were evaluated to critically benchmark performance. Highly sensitive median limits of detection (LODs) with 0.04 μM for >140 quantitatively assessed endogenous metabolites and 0.08 ng/mL for the >100 model xenobiotics and human estrogens in solvent were obtained. In matrix, the median LOD values were higher with 0.7 ng/mL (urine) and 0.5 ng/mL (plasma) for exogenous chemicals. To prove the dual-column approach’s applicability, real-life urine samples from sub-Saharan Africa (high-exposure scenario) and Europe (low-exposure scenario) were assessed in a targeted and nontargeted manner. Our liquid chromatography high-resolution mass spectrometry (LC-HRMS) approach demonstrates the feasibility of quantitatively and simultaneously assessing the endogenous metabolome and the chemical exposome for the high-throughput measurement of environmental drivers of diseases.

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Introduction

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Since the ‘exposome’ first emerged as a new paradigm in environmental health describing the entirety of all environmental exposures enclosing lifestyle factors throughout a human’s lifespan, (1) its scope has expanded further. In recent definitions, endogenous metabolites involved in biological responses (i.e., the endogenous metabolome) that have been triggered by external exposures are typically included. (2,3)
Liquid chromatography high-resolution mass spectrometry (LC-HRMS)-based approaches promise to more comprehensively elucidate the exposome in future exposome-wide association studies (ExWAS). A broad spectrum of small molecules with diverse chemical properties ranging from endogenous metabolites to environmental xenobiotics can be determined with this technique. External stressors, including xenobiotics and environmental changes, are measured simultaneously as phenotypical changes in response to these exposures. Thus, LC-HRMS is an ideal platform for developing more holistic methods to study the exposome. (4) Its applicability to investigate the impact of environmental toxicants on the endogenous metabolome has previously been showcased. (5,6) Metabolomics has been applied in large metabolome-wide association studies (MWAS) to investigate the biological mechanisms of diseases, their diagnosis and treatment. Several studies succeeded in deriving biological effects from their data, although data interpretation remains a challenge. (7−11) The approach also plays an essential role in biomarker discovery and personalized medicine. (12) However, the study of external stressors and complex environmental exposures is clearly less explored and constitutes the next frontier in the current era of omic-scale exposure measurement and systems toxicology.
Targeted multi-analyte methods are commonly used for human biomonitoring (HBM) of xenobiotics, although most approaches assess only a relatively limited number of different exposure markers or chemical classes. (13−19) However, recent initiatives aim to expand the coverage of such multi-analyte and multi-class HBM methods to a larger range of xenobiotics, e.g., Jamnik et al., (20) who simultaneously assessed more than eighty chemicals many of which have known affinity to the estrogen receptor in relevant biological specimens (blood, urine, and breast milk).
The vast physicochemical diversity of xenobiotics also implies widely varying toxicological effects on humans. The adverse impact of, e.g., mycotoxins, a group of fungal food toxins, range from liver carcinogenicity (aflatoxins), nephrotoxicity (ochratoxin A), and estrogenicity (zearalenone) to the inhibition of protein synthesis and mitochondrial function (trichothecenes). (21) Xenoestrogens may immensely impact hormone homeostasis and endocrine disruption, especially in critical time windows, since they interfere with the endocrine system, partly even at extremely low concentrations. (22,23) Estrogenic chemicals occur, for example naturally in plants (phytoestrogens) like genistein or daidzein and synthetic estrogens may be present in pharmaceuticals, insecticides, and plasticizers. (22,24)
Similar to meaningful population-based metabolome research, also exposomics requires large-scale studies for exposome-wide association studies to draw reliable conclusions. The suggested mean sample size for male fertility was estimated to be 2700 men. (25) Hence, high-throughput methods are urgently needed as time is a limiting factor in large-scale epidemiological investigations. In metabolomics, efforts to increase time efficiency are a current priority. (26,27) For example, the usefulness of a dual-column approach to gain more information about the metabolome and lipidome within a short run time was described by Schwaiger et al. (28) Nevertheless, micro- and nano-flow LC-MS have increased in popularity due to increased sensitivity despite longer run times. (29)
The combined and comprehensive measurement of the metabolome and the exposome is challenging as the concentrations of metabolites, drugs, food constituents, and environmental contaminants span approximately ten orders of magnitude and highly diverse classes of chemicals. (3,30) Here, we present a rapid, high-throughput workflow, combining the analysis of endogenous metabolites and multiple classes of xenobiotics in human urine and plasma. The approach utilizes a dual-column approach with a reversed-phase (RP) and a hydrophilic interaction liquid chromatography (HILIC) column being operated in parallel to cover polar compounds as well as the mostly nonpolar xenobiotics. The exposome coverage was evaluated based on more than 200 highly diverse analytes comprising endogenous metabolites and xenobiotics to prove the power of the new method. The applicability to real-life samples was demonstrated by the analysis of urine samples of test sub-populations from Nigeria and Austria.

Materials and Methods

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Chemicals

A multi-analyte stock solution contained endogenous human metabolites (145 analytes) at 50 μM (median of 9300 ng/mL) and xenobiotics, including estrogenic compounds and human estrogens (106 analytes) at a concentration between 5 and 5000 ng/mL (median 100 ng/mL) was prepared in ACN/water (50:50; v/v) (Figure S1). In the context of this paper, the estrogens are evaluated together with the xenobiotic substances and mentioned accordingly. In addition, 15 different isotopically labeled standards of xenobiotics and a separate 13C- labeled yeast extract (ISOtopic solutions, Vienna) were used as internal standards. A complete list of all analytes is available in the Supporting Information (Table S1). A 24 h pooled urine sample obtained from a healthy female volunteer collected in one day after three days of a low-xenoestrogen/polyphenol diet was chosen as a model matrix in this study since urine is frequently used for assessing chemical exposure. Moreover, as a second model matrix, pooled human Li-heparin plasma was acquired from Innovative Research (Novi). Arylsulfatase/β-glucuronidase from Helix pomatia was purchased from Sigma-Aldrich (Vienna, Austria). All materials were stored at −80 °C prior to extraction. The concentrations of all analytes (xenoestrogens, mycotoxins, endogenous estrogens, and other endogenous metabolites) in the calibration standards (8 levels) are listed in the Supporting Information (Table S2).

Samples

For the optimization of the eluent/column combination, a solvent standard and a matrix-matched standard at a medium concentration range (Level 6; Table S2) were used. SRM1950 (Metabolites in Frozen Human Plasma) and SRM3672 (Organic Contaminants in Smoker’s Urine) were purchased from the National Institute of Standards & Technology (NIST, Gaithersburg). In addition, 24 h urine samples from a food intervention study performed in 2021 with four individuals (two females and two males) collected at three different time points (three different days) were tested. For details, kindly refer to Oesterle et al. (2022). (31) Furthermore, urine samples from Nigerian women sampled in 2016 were investigated. This longitudinal sample set was already analyzed before on biomarkers of mycotoxin exposure. (32) Therefore, not all samples from the original study were available due to limited sample volumes. The sample set included 77 spot urine specimens from four time points (morning and evening over two days) of 23 mothers. All samples were stored at −80 °C until analysis. The Nigerian study was approved by the Ethics committee of Babcock University in Nigeria (BUHREC294/16) and the Austrian samples were collected following approval by the University of Vienna ethics committee under authorization number #00650.

Sample Preparation

During the whole sample preparation procedure, the samples were kept on ice. At first, 200 μL of urine or plasma was mixed with 20 μL of the internal standard mix (Table S3) and 20 μL of the 13C-labeled yeast metabolite extract. For the experiment to determine the best solvent/column combination no internal standard was used. Therefore, only 40 μL of H2O was used instead of the internal standard mix. The samples were then vortexed. Afterward, the samples were mixed with 760 μL of the extraction solvent (ACN/ MeOH (1:1, v/v)). After thoroughly vortexing and sonication in an ice bath (10 min), the samples were placed at −20 °C for 2 h and centrifuged at 18,000g and 4 °C (10 min), and 960 μL of the supernatant was transferred to a new tube. Then, the samples were evaporated in a vacuum concentrator (Labconco). The residues were reconstituted in 192 μL of solvent (ACN/ water, 50:50, v/v), vortexed, and centrifuged at 4 °C for 10 min. Finally, the supernatants were transferred to HPLC vials and stored at −80 °C until analysis. Moreover, matrix-matched calibration standards for urine and plasma were prepared by reconstituting matrix extraction according to the sample preparation protocol with respective solvent standard solutions. SRM3672 was additionally treated with β-glucuronidase/arylsulfatase enzymes from Helix pomatia for 12 h at 37 °C prior to extraction as the NIST-certified reference values are given for deconjugated samples. This additional step was not performed for the other samples because the heat treatment would have disturbed the measurements of endogenous metabolites. A nondeconjugated sample was prepared for the SRM material for comparison as well.

Quality Control Measures

As quality control samples, SRM1950 in one to ten dilutions and a solvent QC comprising all target analytes at 1 μM (median of 186 ng/mL, metabolites) and approximately 100 ng/mL (xenobiotics) were analyzed throughout the sequence. Moreover, 10 μL of each urine sample was pooled together for the Austrian and Nigerian samples separately. This pooled urine sample from the Austrian study was measured every nine injections while measuring these samples. The Nigerian pooled urine sample was injected repeatedly with a maximum of nine individual samples in between to check the instrument performance. Solvent blanks (pure reconstitution solvent) and system blanks (200 μL of water extracted according to the sample preparation protocol) were measured to correct for contaminations in the system and during sample preparation.

LC-HRMS(/MS) Analysis

A Vanquish Duo UHPLC system with two independent pumping systems and two different columns was used to optimize chromatographic separation for our highly diverse set of endogenous and exogenous analytes. Different column/eluent systems were examined. The RP gradient was derived from Jamnik et al. (20) and the HILIC gradient was based on Schwaiger et al., (28) Narduzzi et al. (33) and Galvez et al. (34) The NH4F concentration in the aqueous RP eluent was increased to 0.6 mM NH4F to ensure at least 0.3 mM NH4F after dilution with the effluent from the other column before introduction to the MS. If NH4F was used in both eluents, the modifier’s concentration was increased to in total 2 mM NH4F as Narduzzi et al. (33) used this concentration for the HILIC gradient. As a reverse-phase column (RP), the Acquity HSS T3 (Waters, 1.8 μm, 100 mm × 2.1 mm) was used. For HILIC chromatography, two different hydrophilic interaction liquid chromatography columns (HILIC) were used, namely, a SeQuant ZIC-pHILIC (Merck, 5 μm, polymeric, 150 mm × 2.1 mm) and an Acquity BEH Amide (Waters, 1.8 μm, 100 mm × 2.1 mm). Eluent B was in all cases 100% ACN. The aqueous eluent (solvent A) was changed as stated in Table 1. The selection of the NH4F concentration in the aqueous HILIC eluent was based on Narduzzi et al. (33) at either 1 or 2 mM. The injection volume was 5 μL for all columns and experiments.
Table 1. Optimization Design of the Tested Column/Eluent Systems for the Dual-Column Approach
 combination 1combination 2combination 3combination 4
 RP
columnAcquity HSS T3
aqueous eluent0.6 mM NH4F in H2O0.3 mM NH4F in H2O1 mM NH4F in H2O0.6 mM NH4F in H2O
organic eluentACN
 HILIC
columnSeQuant ZIC-pHILICAcquity BEH amide
aqueous eluent10 mM NH4HCO3 (pH 9.2) in H2O/ACN (9:1, v/v)2 mM NH4F in H2O1 mM NH4F in H2O50 mM CH3COONH4 (pH 6) in H2O
organic eluentACN
For the RP measurements, the gradient was as follows: 0–1 min, constant flow at 10% B; 1–10 min, increase to 70% B; 10–11 min, increase to 100% B, and 13.5–15 min, equilibration at 10% B. A hydrophilic interaction liquid chromatography (HILIC) column, SeQuant ZIC-pHILIC (5 μm, polymeric, 150 mm × 2.1 mm), was operated with the following gradient: 0–1 min, constant flow at 75% B; 1–6 min, linear decrease to 50%; 6–7 min, decrease to 30% B; 7–11 min, constant flow at 30%; 11–15 min, equilibration at 75% B. Both columns were at 40 °C and a flow rate of 0.3 mL/min was set. The Acquity BEH Amide was operated with a slightly different gradient as follows: 0–2 min, constant at 80% B; 2–8 min decrease to 40% B; 8–10 min, constant at 40% B and 10–15 min, equilibration at 80% B. Both capillaries were connected with a T-piece to mix the effluents before introduction into the ESI source of the mass spectrometer (Figure 1A). As needle wash, 75% ACN was used for the HILIC measurement, while H2O:ACN: MeOH (2:1:1,v/v/v) was applied for the RP run.

Figure 1

Figure 1. Dual-column setup (A) LC-HRMS system comprising two separate LC-pumps and columns combined by a T-piece before entering the mass spectrometer. (B) Gradients of both individual columns. (C) Eluent composition entering the mass spectrometer after the effluents were mixed.

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Measurements were conducted in fast polarity-switching full scan mode on a Q Exactive HF quadrupole-Orbitrap mass spectrometer. The settings of the ESI interface were as follows: sheath gas, 48 au; auxiliary gas, 11 au; sweep gas flow, 2 au; capillary voltage, 3.5 kV (positive), 2.8 kV (negative); capillary temperature, 260 °C; auxiliary gas heater, 410 °C. The scan range was from 65 to 900 m/z. For full scan-only measurements, the resolution was set to 60,000 with an AGC target (automatic gain control) of 1 × 106 and a maximum injection time of 200 ms. The instrument was calibrated before analysis.
Following the optimization of chromatographic conditions, the most suitable RP/HILIC combination was selected. Consequently, the parameters mentioned above for combination two (Figure 1B) were applied for the sample measurement. A mixture of both effluents entered the mass spectrometer via the ESI source (Figure 1C). For analyses with data-dependent MS2, a resolution of 60,000 with an AGC target of 1 × 106 and a maximum injection time of 100 ms were chosen for the full scan. The settings for the MS2 collection were as follows: resolution, 30,000; AGC target, 1 × 105; maximum injection time, 50 ms, loop count, 10; isolation window, 1.0 m/z; normalized collision energy, 30 eV; minimum AGC, 8 × 103; dynamic exclusion, 4 s. Iterative exclusion lists were generated with IE-Omics. (35) The urine samples from Nigeria and Austria were analyzed in a randomized order.

Data Analysis

Skyline (version 20.2.0.286, (36)) was used for targeted analysis and quantification. The peak retained on the HILIC column was used for the quantification of endogenous metabolites (excluding estrogens) while for xenobiotics the RP peak was chosen in this work. The respective peak was selected based on the retention time derived from injecting only on one column. The other peak (usually the first, less retained one) was not used for our evaluation. An internal standard correction was performed. If no internal standard was included for the specific analyte, the internal standard with the closest retention time was selected as a surrogate standard for normalization (Table S7). The linear calibration curves (Table S7) were 1/x weighted. Matrix-matched calibration for urine and plasma was performed and the corresponding calibration curves were used for the quantification of xenobiotics and human estrogens. However, endogenous metabolites were, as expected, frequently highly abundant in the matrices. Therefore a solvent calibration was applied for endogenous metabolites (excluding estrogens). The creatinine levels were quantitated by one-point calibration based on the creatinine level in SRM3672 (734 mg/L). The limits of detection (LODs) were determined based on the EURACHEM guideline (37) as three times the standard deviation of multiple injections of a less-concentrated standard (n = 6) divided by the square root of the number of replicates. For the limit of quantification (LOQ), the tenfold standard deviation was used. The recoveries were calculated by dividing the spiked concentration by the measured concentration multiplied by 100. The expected concentration level in the spiked samples used for recovery calculation corresponded to standard level 6.
Superman correlation was calculated for compounds positive in at least 20% of all Nigerian samples with R and plotted using the corrplot package (version 0.90). (38) MetaboAnalyst 5.0 Pang et al. (2021) was used for pathway analysis. (39) A hypergeometric test was selected as an enrichment method and for topology analysis relative-betweenness centrality. The pathway library was Homo sapiens (KEGG).
The pooled Nigerian urine sample, including MS2 data measured in negative and positive ionization mode with iterative exclusion lists (n = 4), was used to screen for potential additional xenobiotics not covered by the targeted evaluation using authentic reference standards. Suspect screening was performed in R, applying the patRoon package. (40) Solvent process blanks (only in the corresponding polarity) were defined as blank measurements. The raw data files were converted to mzML files and centroided with ProteoWizard. (41) For peak picking and grouping, the “openms” algorithm was set with the following parameters: noise threshold: 4E3, chromFWHM: 3, minFWHM: 1, maxFWHM: 30, chromSNR: 5, and mzPPM: 3. Only features with a minimum absolute feature intensity of 3E5, a minimum feature intensity above blank of 10, present in at least 60% of replicates, were kept and blank analyses were removed after this step. A suspect list from the ENTACT trial (42) based on the EPA’s ToxCast library, including >4000 substances, was adopted for this experiment. Analytes, which had already been included in the targeted list were removed to avoid redundancy. For suspect screening, an m/z window of 0.002 was set. MS peak list data were extracted with the mzr algorithm (precursor m/z window: 0.5) and filtered (relative intensity threshold: 0.02, top 10 MS/MS peaks). Then molecular formulas were generated considering [M + H]+ and [M – H]− adducts, and the elements C, H, N, O, P, S, Cl, Br using genform. Chemical compounds were annotated with metfrag and the comptox database. The suspect screening results were refined using annotateSuspects and the generated peak lists, formula, and compound data. An identification level was assigned depending on the rank and scores (isoScore, individualMoNAScore) of formula/compound candidates based on Schymanski et al. (43) The default settings in the annotateSuspects algorithm were applied. As no retention time data were available, level one identifications were not possible. The other identification levels were: level 2a (good MS/MS library match, top-ranked in compound results, individualMoNAScore ≥ 0.9, no MoNA library score for other candidates), level 3a (fair library match, individualMoNAScore ≥ 0.4), level 3b (known MS/MS match, at least three fragment match), level 3c (good in silico MS/MS match, annotation MS/MS similarity (annSimComp) ≥ 0.7), level 4a (good formula MS/MS match, top-ranked formula candidate, annSimForm ≥ 0.7, isotopic match (isoScore) ≥ 0.5, both scores at least 0.2 higher than next best-ranked candidate), level 4b (good formula isotopic pattern match, top-ranked formula candidate, isoScore ≥ 0.9, score at least 0.2 higher than the next best-ranked candidate) and level 5 (nothing of the abovementioned criteria match).

Results and Discussion

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Establishing a Dual-Column Approach for Combined Exposure and Effect Analysis

Selection of Columns and Eluents

In optimization experiments, different eluent–column combinations were tested for the best overall performance and compatibility. Only eluents with a basic (pH 9.2) to slightly acidic pH (pH 6) were combined with NH4F to avoid the formation of hydrofluoric acid. For a representative selection of selected compounds (25 metabolites on the HILIC column and 25 xenobiotics and human estrogen metabolites on the RP column), the averaged peak area (n = 4–6) in a matrix-matched standard (urine) and a solvent standard both at a medium concentration level (level 6) were compared between the combinations (Figure 2 and Table S4). Peak areas were normalized to the best combination for each analyte to simplify the comparison. Endogenous metabolites are frequently naturally present in urine at high abundances. Therefore, the peak areas in the standard-spiked urine increased compared to the solvent standards. The observed signal was mostly decreased for xenobiotics due to signal suppression in the urine matrix. The averaged peak areas of the selected metabolites showed that the combination of 2 mM NH4F/ACN on a SeQuant ZIC-pHILIC column (HILIC) and 0.3 mM NH4F/ACN on an Acquity HSS T3 column is favorable (highest peak area) in the solvent. However, the difference between the three others is only minor, with combination 2 reaching about 85% of the average peak area of combination 1. In urine, the average peak area of combination 4, which uses an Acquity BEH amide column instead of a SeQuant ZIC-pHILIC column, is only about half of the others. Except for combination 4, all eluent–column combinations performed similarly, but with combinations 2 and 3, both using NH4F as an additive, up to four metabolites (choline, phosphocreatine, citric acid, 3-methylcytidine) were not detectable at the chosen concentration level. Therefore the SeQuantZIC-pHILIC column with a basic NH4CO3 buffer based on Schwaiger et al. (28) seemed to be the best choice regarding endogenous metabolites excluding estrogen hormones. When xenobiotics and endogenous estrogen metabolites were investigated, however, the additive NH4F clearly outperformed the basic buffer. The average peak area in urine and solvent of this group nearly doubled when NH4F was used. Since xenobiotics are generally less concentrated than metabolites in real-life samples, we decided to use this additive to boost their sensitivity and finally selected the combination with 2 mM NH4F as the aqueous HILIC eluent and 0.3 mM NH4F as the aqueous RP column eluent due to better overall performance.

Figure 2

Figure 2. Comparison of the averaged peak areas of selected representative endogenous metabolites (n = 25) (A) and xenobiotics, including estrogen hormone metabolites (n = 25) (B) in solvent and urine, including a detailed overview of the averaged peak areas) relative to the highest peak area of the individual molecule from replicate injections of the samples areas (n = 4 (Comb. 4, Comb. 1); n = 6 (Comb.1, Comb. 2). The best overall combination is shaded in gray. Different columns, namely Acquity HSS T3 (HSS), SeQuant ZIC-pHILIC (ZIC), Acquity BEH Amide (BEH), and eluents, namely 0.3/0.6/1/2 mM NH4F in H2O (0.3/0.6/1/2 mM NH4F), 10 mM NH4HCO3 (pH 9.2) in H2O/ACN (9:1, v/v) (10 mM NH4HCO3), and 50 mM CH3COONH4 (pH 6) in H2O (50 mM HAc) were tested.

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Long-Term Stability of the LC-MS Setup

A solvent QC sample containing endogenous metabolites at 1 μM (median of 186 ng/mL) and xenobiotics including human estrogens at approximately 100 ng/mL was injected throughout the sequence (n = 11), spanning over a period of 40 h. Only the most abundant ion species were considered. The peaks from the HILIC column were evaluated for assessing endogenous metabolites and the peaks from the reversed-phase column for evaluating xenobiotics and human estrogens. At the chosen concentration level, 113 out of the 146 metabolites (77%) were retained with a retention time bigger than 1 min on the HILIC column and 104 out of the 106 xenobiotics and human estrogens (98%) with retention on the RP column (retention time > 0.8 min) were detectable. Four analytes were not detectable even at higher levels. The relative standard deviation (RSD) was calculated for the peak area and the retention of all detectable molecules at this level (Figure 3A,B). The median RSDs of the area were 22 and 31% in the negative and positive ionization modes, respectively. The difference between peaks from the HILIC and RP separation was minor, but in the positive ionization mode, the relative standard deviation of the area was generally bigger. Regarding retention time, the median RSD was 0.4% for the negative mode and 0.7% for the positive mode. Xenobiotics’ times were more stable with a median of 0.3 compared to 1.3% for the endogenous metabolites. The retention time of some endogenous phosphates and acids, analyzed mainly in the negative ionization mode, was shifted significantly during the sequence as the buffer capacity of the NH4F eluent was low. The variation of the retention time and area of the most abundant ion species for the respective analytes is also presented in quality control charts (Figure S12).

Figure 3

Figure 3. Repeatability and accuracy in a solvent QC sample (1 μM for metabolites and xenobiotics at approximately 100 ng/mL) are reported as the number of analytes within a certain relative standard deviation of the (A) peak area and (B) retention time. The lines mark the thresholds and the labels indicate how many analytes fall below a respective RSD percentage. Only the most abundant ion species was considered for the respective column. (C) Analytes reported in SRM3672 and (D) in SRM1950 with the gray line indicating the certified reference value and the expanded uncertainty according to the certificate of analysis.

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Pooled quality control samples of both sample sets were measured several times throughout the measurement (Figure S2). The relative standard deviation of the retention time and the normalized peak area was calculated for highly diverse analytes. This included bisphenol A (BPA), daidzein, enterodiol, glycitein, methylparaben, and triclosan in the pooled urine of the Nigerian samples (n = 9) and BPA, daidzein, nonylphenol and p-hydroxybenzoic acid in the pooled urine of the Austrian samples (n=5). In addition, four metabolites (tryptophan, uracil, fumaric acid, gluconate) were investigated. The relative standard deviation of the retention time was <1.5% for all analytes except for fumaric acid (about 2.8%). The relative standard deviation of the normalized area was <20% for all six analytes except for BPA (22%), which was present at a low concentration around the LOD in the Austrian pooled urine sample. The variation tended to be lower if the corresponding 13C-labeled compound was available for compound-specific internal standardization (e.g., for methylparaben) as compared to surrogate internal standardization. A PCA plot of the Austrian and Nigerian pooled QC sample respectively shows clustering of the respective pooled urine sample (Figure S13).

Quantification of Reference Materials

The limits of detection for the xenobiotics and human estrogens ranged from 0.01 to 5.7 ng/mL with a median of 0.08 ng/mL in the solvent (Table S5 and Figure 4C). In the matrix, the median LOD increased to 0.7 (urine, Figure 4A) and 0.5 (plasma, Figure 4B) most likely due to matrix effects and matrix interferences. Phytoestrogens like daidzein and genistein and personal care product ingredients, e.g., parabens, exhibited the lowest LODs. The LODs were, for most xenobiotics and human estrogens, sufficient to detect them in averagely contaminated samples considering concentration levels from published human biomonitoring studies (Table S21).

Figure 4

Figure 4. Limit of detection (LOD) of representative xenobiotics and estrogens in urine (A), plasma (B), and neat solvent (C) sorted by compound classification. The values were plotted on a logarithmic scale. (D) Number of endogenous metabolites in a specific LOD range. The color indicates the category to which the analytes can be classified to.

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Six analytes for which certified reference values are available in SRM3672 (Organic Contaminants in Smoker’s Urine) were detected and quantified (Table S13). As the values stated in the certificate were total analyte concentrations after hydrolysis, β-glucuronidase/arylsulfatase-treated reference urine was analyzed. The relative error compared to the reference value was <20% for all of these (Figure 3C). 1-OH-pyrene and MEHP were not detected, although they were present in smokers’ urine, due to their low concentration below method’s quantification limits. In addition to several amino acids, PFOA and PFOS were quantified in SRM1950 (Metabolites in Frozen Human Plasma) and compared to the certificate (Figure 3D and Table S14). Threonine was not evaluated as it coeluted with homoserine; therefore, only a combined value for both amino acids was available. Isoleucine and leucine were not baseline separated as well, but for both molecules, reference values were given. Therefore the sum of both concentrations was compared. The relative error was <26% for all amino acids, whereby the recoveries were in general lower for the high-abundance amino acids (glycine (75%), alanine (82%), isoleucine/leucine (74%)), possibly due to saturation effects as the values were outside of the calibration range (Figure 3D). The samples were injected undiluted to ensure high detectability of less-concentrated xenobiotics despite possible saturation issues for the endogenous metabolites at higher concentrations. The relative errors of PFOA and PFOS were even <5 and <20%, respectively. In general, the determined values were in good agreement with the reference values of both SRMs, especially given the extensive scope of the new workflow with recoveries ranging from 74 to 124% in SRM1950 and recoveries between 81 and 115% in SRM3672 (Figure 3C). These recoveries are similar to values reported in the literature for SRM3672 by Karthikraj et al. (44) (80.5–105%) and Zhu et al. (45) (80–111%).
In the reference materials, several additional metabolites and xenobiotics were quantified (Figure S3 and Table S16). In SRM3672, 18 xenobiotics and two estrogens were detected. SRM1950 was contaminated with 17 xenobiotics, with nine of them being detected in both reference materials, including personal care product ingredients (methylparaben, propylparaben, p-hydroxybenzoic acid, benzophenone-1), phytoestrogens (genistein, daidzein), smoking markers (cotinine, trans-3-OH-cotinine), and an industrial side product (2-naphthol). In SRM3672, additional phytoestrogens (e.g., enterolactone, enterodiol, daidzein, glycitein), a plasticizer (monobutyl phthalate), and butylparaben were observed, whereas, in SRM1950, scopolamine, a phytotoxin, perfluorinated substances (PFOA, PFOS), industrial side products (nonylphenol, 4-tert-octylphenol) and other plasticizers (BPS, BPA) were found. The quantified metabolome comprised 48 (SRM1950) and 61 (SRM3672) additional compounds, respectively. Smoker’s urine was not enzyme-treated for this evaluation. Mainly amino acids, nucleobases, and nucleosides were quantified in these samples. The concentrations ranged over four orders of magnitude for metabolites in the urine plasma reference material. This range spanned even over six orders of magnitude when expanding to exogenous contaminants. In the urine reference material, concentrations were less variable covering three orders of magnitude.

Analytical Parameters

The linear dynamic range was highly variable and depended on the investigated molecule (Table S19). About 10% of the xenobiotics and human estrogens had a linear range spanning five orders of magnitude. Half of them covered a range of four and approximately a third a range of three orders of magnitude in the solvent. Matrix matching typically reduced the dynamic range by about one order of magnitude due to matrix effects, as the LOD of the xenobiotics and human estrogens in the matrix was generally lower.
The accuracy in a solvent standard compared to the expected concentration at level 6 ranged in solvent between 83 and 123% with an average of 104% for xenobiotics including human estrogens and 81 and 119% with an average of 101% for endogenous metabolites (Table S19/Table S20). Furthermore, the extraction recoveries were evaluated in spiked urine and plasma samples (Table S19/Table S20). The median recovery of xenobiotics and human estrogens was 97% in urine and 103% in plasma, whereas for metabolites, these figures were determined to be 97 and 99%, respectively. Only 10% of the analytes in urine and 14% in plasma had a recovery below 80%. The recoveries were above 120% for about 1% of compounds in urine and 3% in plasma. Several analytes, especially endogenous metabolites, were already present in high quantities in the nonfortified urine and plasma. Hence, the extraction recovery was not estimated for all compounds.
The solvent LODs of endogenous metabolites ranged from 0.001 μM (0.2 ng/mL) to 6.6 μM (1068 ng/mL) with a median of 0.04 μM (8 ng/mL) (Table S6 and Figure 4D). The LOD values were estimated for 134 analytes, including several jointly evaluated isomers. Due to their high natural abundance, the LOD of several endogenous metabolites was not estimated in the human matrices. About one-third of all compounds showed LODs <0.01 μM (approximately 1.9 ng/mL) and about two-thirds <0.1 μM (approximately 19 ng/mL) allowing for the straightforward (semi-) quantitative assessment of the metabolome in most biological systems. The reference standards spanned five orders of magnitude, from 0.001 to 10 μM. However, most metabolites were not detectable at the lower calibration level (0.001–0.01 μM), limiting the linear dynamic range to four (45%), three (29%) or even less (8%) orders of magnitude (Table S20).

Limitations

Out of the 145 endogenous metabolites in the standard mix, five (1-methylnicotinamide, thiamine, choline, spermine, and spermidine) were not detectable even at the highest concentration level (10 μM, approximately 1860 ng/mL). Isomers were not separated in some cases. These included 2-/3-phosphoglyceric acid, citric/isocitric acid, homoserine/threonine, and isoguanosine/guanosine. The hexoses fructose, galactose, mannose, glucose, and inositol were not distinguishable, as well as their phosphates (fructose-6-phosphate, glucose-1-phosphate, and glucose-6-phosphate) as they were coeluting and therefore the peaks were not baseline separated. Pentose-phosphates, ribose-5-phosphate, and ribulose-5-phosphate were not baseline separated too. For arginine and palmitic acid, no satisfactory linear regression was achieved, most likely due to severe carryover effects. The setup of the dual-column approach is simple but requires two independent pumps. Thus, our dual-column approach might not be transferable to another laboratory without acquiring specific equipment before. A limitation of our study was the selection of real-life samples as both sample sets are not matched in size, demographic background, and storage duration. However, these samples still have the power to showcase the unique capacities of the developed approach to detect various chemicals from endogenous and exogenous sources. Moreover, only a single reference material was analyzed as the experimental sample for plasma. Nonetheless, we could identify over 60 chemicals in this plasma sample showing highly convincing performance for this matrix.
The combination of the column effluents before introduction to the MS increases the amount of coeluting compounds, potentially causing elevated matrix effects. At the same time, the sample is diluted as the flow is doubled before the analysis.
Internal standard normalization was applied for quantification. Since the set of labeled standards was limited, partially surrogate internal standards were applied reducing the reliability of normalization for these analytes.
The concentrations in the urine samples were not normalized to the creatinine level, thus the varying matrix dilution might cause varying matrix effects impacting the analysis

Application in Biomonitoring Studies from Europe and Sub-Saharan Africa

The established analysis pipeline was applied in proof-of-principle studies of two different urine sample sets from geographically different areas, Austria and Nigeria. Both studies included several individuals who donated samples at four different time points. In the Austrian samples, 17 different xenobiotics belonging to four compound categories were identified (Figure S5A/B and Table S10). Most exposures were either personal care product ingredients or phytoestrogens. The Nigerian urine samples were contaminated with more than twice as many chemicals (n = 48) coming from diverse sources (Figure 5A and Table S9), but personal care product ingredients and phytoestrogens were still the dominant classes. Concentrations covered five orders of magnitude from the sub-ppb to the ppm range. The Nigerian samples were contaminated with a broader diversity of chemicals, including air pollutants (1-OH-pyrene), mycoestrogens (ZEN, AME), and industrial side products (2-naphthol) at higher concentration levels. In particular, the maximum values were frequently 10–100-times higher than the Austrian samples. However, especially the Austrian dataset was small and homogenous compared to the Nigerian dataset. Moreover, the demographic data of the individuals involved in both studies and storage times varied and the stability of analytes was not specifically assessed in this work. Therefore, the available data are not sufficiently representative to estimate population-wide exposure levels. However, the results highlight the potential of the dual-column approach to capture environmental contaminants in different urine samples. The Austrian samples were considered a low-exposure scenario due to strict regulation and enforcement on the use/tolerance of e.g., pesticides and mycotoxins, whereas the Nigerian samples were regarded as high-exposure samples as often food/environmental safety regulations are lacking or not adequately enforced. Each detected xenobiotic was, on average, detected in 31 out of 77 Nigerian samples. Four analytes (enterolactone, BPA, nonylphenol, and propylparaben) were present in >90% of all samples (Figure 5B). In the Austrian samples, two-thirds were positive for daidzein, 4-tert-octylphenol, BPA, and propylparaben. In addition, all samples contained nonylphenol and dibutyl phthalate. MS2 spectra further supported identification (Figure 5C), although for all analytes discovered here reference standards were used for retention time confirmation (level 1 identifications). The number and level of the detected phytoestrogens were restricted due to the regulated diet with no vegetable and fruit intake except for a smoothie on day 2 before the Austrian study and on the first two study days. Approximately 70 diverse endogenous metabolites were quantified in the urine samples of both studies (Tables S11 and S12). Thirteen individuals completed the full longitudinal sampling with four time points. The variation over two days is exemplified for six individuals and analytes of distinct origins, including the plasticizer bisphenol A, the phytoestrogen genistein, the personal care product ingredient propylparaben and the air pollutant 1-OH-pyrene in Figure 5D. The concentrations spanned over three orders of magnitude within the individual sample. Genistein and propylparaben differed vastly between the time points in particular. The intraindividual variation was like the interindividual variation demonstrating the importance of longitudinal sampling for exposure assessment of several participants. The diversity and high dynamics of the exposome even within the same individual were described previously (46) and further supported the need for time-resolved testing to capture dynamic exposure in spot urine samples or 24 h urine.

Figure 5

Figure 5. Detection of xenobiotics and endogenous estrogens in Nigerian samples. (A) Variety of observed xenobiotics including human estrogens and their classification. (B) Individual concentrations of selected analytes that have been detected in > 50% of the samples (n = 77). The human biomonitoring (HBM) guidance value for BPA (47) was added in red. (C) Extracted ion chromatograms (XICs) of selected analytes, including corresponding MS2 spectra of experimental samples and authentic reference standards. (D) Variation of analyte concentration in six individuals for selected xenobiotics demonstrates severe exposure dynamics and the need for longitudinal sampling design.

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A Spearman correlation matrix was created to showcase the power of our approach for deriving possible impacts of exogenous exposures on the endogenous metabolites that are of high interest for further thorough mechanistic studies. Various significant correlations between xenobiotics and also between xenobiotics and metabolites were demonstrated (Figure S4). Mainly analytes detected in many samples, e.g., monobutyl phthalate, ethylparaben, MEHP, benzophenone, and enterolactone, yielded significant correlations, probably due to the higher statistical power. High-correlation coefficients were observed for monobutyl phthalate and MEHP (0.72), ethylparaben and p-hydroxybenzoic acid (0.64), benzophenone-1 and enterolactone (0.74), and propylparaben and methylparaben (0.59). MEHP and monobutyl phthalate are both urinary biomarkers of phthalate exposure. (48) The preservatives ethylparaben and p-hydroxybenzoic acid were likely to be an ingredient in the same type of personal care products and also methylparaben and ethylparaben may be present in similar products. Enterolactone, a biotransformation product of plant lignans originating from, e.g., flaxseeds and sesame, (49) and the urinary biotransformation product of benzophenone-3, benzophenone-1, a UV-filter used in cosmetics, (50) clearly have different sources. However, both are hormonally active and have a shared mechanism concerning obesity antagonism. This was demonstrated to be associated with late onset of puberty in girls. (51)
The link between external exposures and the ensuing disturbance of the internal metabolome is one step to elucidating disease development, which is part of the broad scope of exposome research. With our approach, connections between xenobiotics and metabolites were indicated. A strong correlation between ethylparaben and the carboxylic acids, fumaric acid (0.68) and malic acid (0.67) and the amino acid alanine (0.62) were uncovered. Alanine (0.64), fumaric acid (0.63) and malic acid (0.6) were connected to benzophenone-1, too. The matrix also strongly correlated monobutyl phthalate and aspartic acid (0.66). These correlations highlight potentially interesting links between the exposome and the metabolome and might be seen as a starting point for deciphering causal connections. Additional, in-depth experiments will be necessary to prove these links in future ExWAS investigations.
However, in the literature some exposed correlations have already been reported. Phthalate exposure was associated with altered carnitine levels and changes in metabolites associated with amino acid metabolism in the urine of Chinese men. (52) In our study, carnitine, propionyl carnitine, and several amino acids were also correlated with monobutyl phthalate. Pathway analysis was performed for significantly correlated metabolites with monobutyl phthalate (Figure S6). The results revealed a potentially strong impact on alanine, aspartate, and glutamate metabolism, arginine biosynthesis, and the citrate cycle. The pathway analysis of ethylparaben-associated metabolites showed similar results, with arginine biosynthesis and alanine, aspartate, and glutamate metabolism being the most affected pathways (Figure S7). These two pathways were also the most affected along with benzophenone-1 correlated metabolites (Figure S8). The xenobiotics benzophenone-1, monobutyl phthalate, and ethylparaben exhibited a moderate correlation (correlation coefficient between 0.5 and 0.64) among each other, therefore, the disturbance in amino acid metabolism might not be triggered by a single compound but rather by a mixture of different chemicals. Further investigations are needed to support our preliminary observations.
Recent studies demonstrated the feasibility of exposome-wide association studies (ExWAS), e.g., extensive effect biomarker and biomarker discovery of air pollutant exposure (53) and linking metabolic profiling and exposure to perfluoroalkyl substances. (54) However, several independent measurements were required to capture the metabolome and chemical exposome, increasing the measurement time compared to our 15 min LC-HRMS/MS run covering both polar metabolites and the primarily non-polar xenobiotics. Especially, molecules with high vapor pressure and low boiling/melting point were not accessible with LC-MS technology. Therefore, GC-MS would need to be integrated to further extend coverage. (55,56) Although our fast LC-MS approach might be advantageous regarding run time, the vast concentration difference between endogenous metabolites and environmental contaminants (30) hamper their simultaneous measurement as several endogenous metabolites were close to the detector saturation and less-abundant xenobiotics still need higher sensitivity. In particular, quantification posed a challenge, as calibration ranges were partially exceeded. Internal standard correction eased linearity issues especially at high concentrations as it compensates for increasing ion suppression and detector saturation.

Suspect Screening in Biological Samples Obtained from Nigerian Women

Raw data from four pooled Nigerian urine samples with iterative MS2 exclusion lists were processed for suspect screening to demonstrate the workflow’s suitability for suspect and nontargeted screening/analysis (NTS/NTA). On average, 14,126 and 18,408 features were picked in each sample in the negative mode and positive mode, respectively; 16,288 negative features in 4590 groups remained after removing features present in the blank and applying an intensity and replicate abundance filter. In the positive ionization mode, 21,384 features in 5937 groups remained after filtering. Features were included if they were present in at least 3 out of 4 replicates. Therefore the feature number after the filter application was higher than that in the individual sample. A match with the suspect list was found for 706 (positive) and 749 (negative) peaks. The suspect list contained several isomers. Therefore in some cases, various molecules were suggested as an annotation. Altogether, 1238 different compounds, partly observed in both ionization modes, were proposed as potential annotations for the feature groups. Identification levels 1–4 were established for 52% (370) and 58% (435) in positive and negative ionization modes, respectively (Tables S17 and S18). MS2 matches (level ≥ 3c) were obtained for 187 (positive mode) and 190 (negative mode) feature groups. The annotation of 377 feature groups in both ionization modes with an identification level of at least 3c was successful, consequently showcasing the workflow’s ability to detect analytes without available reference standards and capture additional compounds potentially present in the samples.

Conclusions

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The presented workflow facilitates the rapid and simultaneous exploration of complex environmental exposures and their effect on the human metabolome. Despite issues due to the wide concentration range, the quantification of several endogenous metabolites and exogenous chemicals acquired simultaneously in one short LC-MS/MS run succeeded and preliminary correlations between metabolites and chemicals were revealed. Consequently, the potential effects of specific exposures on the metabolome were directly derived from exposure data in a unique way. However, further experiments are required to establish solid causal relationships. Combining two columns and both ionization modes in one single data file drastically decreased measurement time and simplified data evaluation and storage requirements. For deciphering the exposome, hundreds to thousands of samples will be needed to be analyzed. Therefore, the reduced analysis time opens up for so far unseen throughput in exposome-wide association studies for drawing reliable conclusions on the impact of environmental factors on disease development.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.2c00433.

  • Supporting Information A: visualization of the diversity of selected model molecules, normalized peak areas of QC samples, concentrations of noncertified values in the reference material, Spearman correlation matrix, summary of detected xenobiotics in Austrian urine samples, pathway analyses, total ion chromatograms, summary of molecules in a multi-analyte mixture and their concentrations including internal standards, average peak areas of analytes for different eluent/column combinations, limits of detection and retention times of analytes, calibration parameters, and linear dynamic ranges and recoveries of analytes (PDF)

  • Supporting Information B: detailed results of Nigerian and Austrian urine analysis, concentrations of certified values in reference materials, results of suspect screening approach, creatinine levels of urine samples, selected extracted ion chromatograms, quality control charts, PCA plots, and peak areas of pooled QC sample over several injections (XLSX)

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Author Information

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  • Corresponding Author
    • Benedikt Warth - Faculty of Chemistry, Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria;  Exposome Austria, Research Infrastructure and National EIRENE Hub, 1090 Vienna, Austria;  Orcidhttps://orcid.org/0000-0002-6104-0706;  Email: [email protected]
  • Authors
    • Mira Flasch - Faculty of Chemistry, Department of Food Chemistry and Toxicology, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria;  Vienna Doctoral School of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria;  Orcidhttps://orcid.org/0000-0002-3518-3885
    • Veronika Fitz - Vienna Doctoral School of Chemistry, University of Vienna, Währinger Straße 42, 1090 Vienna, Austria;  Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria
    • Evelyn Rampler - Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria;  Orcidhttps://orcid.org/0000-0002-9429-7663
    • Chibundu N. Ezekiel - Department of Microbiology, Babcock University, 121103 Ilishan Remo, Ogun State, Nigeria;  Orcidhttps://orcid.org/0000-0002-2113-2948
    • Gunda Koellensperger - Faculty of Chemistry, Department of Analytical Chemistry, University of Vienna, Währinger Straße 38-40, 1090 Vienna, Austria;  Exposome Austria, Research Infrastructure and National EIRENE Hub, 1090 Vienna, Austria;  Orcidhttps://orcid.org/0000-0002-1460-4919
  • Author Contributions

    CRediT: Mira Flasch conceptualization, data curation, formal analysis, investigation, methodology, visualization, writing-original draft; Veronika Fitz investigation, methodology, writing-review & editing; Evelyn Rampler methodology, supervision, writing-review & editing; Chibundu N Ezekiel resources, writing-review & editing; Gunda Koellensperger resources, supervision, writing-review & editing; Benedikt Warth conceptualization, funding acquisition, resources, supervision, writing-review & editing.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors greatly appreciate the volunteers donating urine samples and the members of the Warth and Koellensperger labs for critical advice and feedback. The authors would like to thank the Mass Spectrometry Centre (MSC) of the Faculty of Chemistry at the University of Vienna for technical support. This study was financed by the University of Vienna and supported by the ESFRI Research Infrastructure EIRENE. The data are freely available via the MetaboLights repository (MTBLS4556).

References

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    A review. Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chems. undergo metab. and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metab. or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to det. the full metabolic effects that these chems. have on the body. Metabolomics, the comprehensive anal. of small mols. in a biofluid, can reveal biol. relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, pos. and neg., with xenobiotic metab.
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  7. 7
    Garratt, M.; Lagerborg, K. A.; Tsai, Y.-M.; Galecki, A.; Jain, M.; Miller, R. A. Male lifespan extension with 17-α estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice. Aging Cell 2018, 17, e12786  DOI: 10.1111/acel.12786
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    Reinke, S. N.; Gallart-Ayala, H.; Gómez, C. Metabolomics analysis identifies different metabotypes of asthma severity. Eur. Respir. J. 2017, 49, 1601740  DOI: 10.1183/13993003.01740-2016
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    There is no corresponding record for this reference.
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    Ganna, A.; Salihovic, S.; Sundström, J. Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease. PLoS Genet. 2014, 10, e1004801  DOI: 10.1371/journal.pgen.1004801
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    Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease
    Ganna, Andrea; Salihovic, Samira; Sundstroem, Johan; Broeckling, Corey D.; Hedman, Aasa K.; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Larsson, Anders; Siegbahn, Agneta; Zilmer, Mihkel; Prenni, Jessica; Aernloev, Johan; Lind, Lars; Fall, Tove; Ingelsson, Erik
    PLoS Genetics (2014), 10 (12), e1004801/1-e1004801/10, 10 pp.CODEN: PGLEB5; ISSN:1553-7404. (Public Library of Science)
    Analyses of circulating metabolites in large prospective epidemiol. studies could lead to improved prediction and better biol. understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for assocn. with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18:1 (hazard ratio [HR] per std. deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18:2 (HR = 0.81, P-value<0.001), monoglyceride 18:2 (MG 18:2; HR = 1.18, P-value = 0.011) and sphingomyelin 28:1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addn. to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18:2 was assocd. with CHD independently of triglycerides. Lysophosphatidylcholines were neg. assocd. with body mass index, C-reactive protein and with less evidence of subclin. cardiovascular disease in addnl. 970 participants; a reverse pattern was obsd. for MG 18:2. MG 18:2 showed an enrichment (P-value = 0.002) of significant assocns. with CHD-assocd. SNPs (P-value = 1.2 × 10-7 for assocn. with rs964184 in the ZNF259/APOA5 region) and a weak, but pos. causal effect (odds ratio = 1.05 per SD increment in MG 18:2, P-value = 0.05) on CHD, as suggested by Mendelian randomization anal. In conclusion, we identified four lipid-related metabolites with evidence for clin. utility, as well as a causal role in CHD development.
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  10. 10
    Rhoades, S. D.; Sengupta, A.; Weljie, A. M. Time is ripe: maturation of metabolomics in chronobiology. Curr. Opin. Biotechnol. 2017, 43, 70– 76,  DOI: 10.1016/j.copbio.2016.09.007
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    Time is ripe: maturation of metabolomics in chronobiology
    Rhoades, Seth D.; Sengupta, Arjun; Weljie, Aalim M.
    Current Opinion in Biotechnology (2017), 43 (), 70-76CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
    A review. Sleep and circadian rhythms studies have recently benefited from metabolomics analyses, uncovering new connections between chronobiol. and metab. From untargeted mass spectrometry to quant. NMR spectroscopy, a diversity of anal. approaches has been applied for biomarker discovery in the field. In this review we consider advances in the application of metabolomics technologies which have uncovered significant effects of sleep and circadian cycles on several metabolites, namely phosphatidylcholine species, medium-chain carnitines, and arom. amino acids. Study design and data processing measures essential for detecting rhythmicity in metabolomics data are also discussed. Future developments in these technologies are anticipated vis-a-vis validating early findings, given metabolomics has only recently entered the ring with other systems biol. assessments in chronometabolism studies.
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  11. 11
    Hu, X.; Walker, D. I.; Liang, Y. A scalable workflow to characterize the human exposome. Nat. Commun. 2021, 12, 5575  DOI: 10.1038/s41467-021-25840-9
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    11
    A scalable workflow to characterize the human exposome
    Hu, Xin; Walker, Douglas I.; Liang, Yongliang; Smith, Matthew Ryan; Orr, Michael L.; Juran, Brian D.; Ma, Chunyu; Uppal, Karan; Koval, Michael; Martin, Greg S.; Neujahr, David C.; Marsit, Carmen J.; Go, Young-Mi; Pennell, Kurt D.; Miller, Gary W.; Lazaridis, Konstantinos N.; Jones, Dean P.
    Nature Communications (2021), 12 (1), 5575CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    Abstr.: Complementing the genome with an understanding of the human exposome is an important challenge for contemporary science and technol. Tens of thousands of chems. are used in commerce, yet cost for targeted environmental chem. anal. limits surveillance to a few hundred known hazards. To overcome limitations which prevent scaling to thousands of chems., we develop a single-step express liq. extn. and gas chromatog. high-resoln. mass spectrometry anal. to operationalize the human exposome. We show that the workflow supports quantification of environmental chems. in human plasma (200 μL) and tissue (≤100 mg) samples. The method also provides high resoln., sensitivity and selectivity for exposome epidemiol. of mass spectral features without a priori knowledge of chem. identity. The simplicity of the method can facilitate harmonization of environmental biomonitoring between labs. and enable population level human exposome research with limited sample vol.
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  12. 12
    Jacob, M.; Lopata, A. L.; Dasouki, M.; Rahman, A. M. A. Metabolomics toward personalized medicine. Mass Spectrom. Rev. 2019, 38, 221– 238,  DOI: 10.1002/mas.21548
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    12
    Metabolomics toward personalized medicine
    Jacob, Minnie; Lopata, Andreas L.; Dasouki, Majed; Abdel Rahman, Anas M.
    Mass Spectrometry Reviews (2019), 38 (3), 221-238CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
    A review. Metabolomics, which is the metabolites profiling in biol. matrixes, is a key tool for biomarker discovery and personalized medicine and has great potential to elucidate the ultimate product of the genomic processes. Over the last decade, metabolomics studies have identified several relevant biomarkers involved in complex clin. phenotypes using diverse biol. systems. Most diseases result in signature metabolic profiles that reflect the sums of external and internal cellular activities. Metabolomics has a major role in clin. practice as it represents >95% of the workload in clin. labs. worldwide. Many of these metabolites require different anal. platforms, such as NMR (NMR), Mass Spectrometry (MS), and Ultra Performance Liq. Chromatog. (UPLC), while many clin. relevant metabolites are still not routinely amenable to detection using currently available assays. Combining metabolomics with genomics, transcriptomics, and proteomics studies will result in a significantly improved understanding of the disease mechanisms and the pathophysiol. of the target clin. phenotype. This comprehensive approach will represent a major step forward toward providing precision medical care, in which individual is accounted for variability in genes, environment, and personal lifestyle. In this review, we compare and evaluate the metabolomics strategies and studies that focus on the discovery of biomarkers that have "personalized" diagnostic, prognostic, and therapeutic value, validated for monitoring disease progression and responses to various management regimens.
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  13. 13
    Prasain, J. K.; Arabshahi, A.; Moore, D. R., 2nd; Greendale, G. A.; Wyss, J. M.; Barnes, S. Simultaneous determination of 11 phytoestrogens in human serum using a 2 min liquid chromatography/tandem mass spectrometry method. J. Chromatogr. B 2010, 878, 994– 1002,  DOI: 10.1016/j.jchromb.2010.02.032
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    13
    Simultaneous determination of 11 phytoestrogens in human serum using a 2 min liquid chromatography/tandem mass spectrometry method
    Prasain, Jeevan K.; Arabshahi, Alireza; Moore, D. Ray; Greendale, Gail A.; Wyss, J. Michael; Barnes, Stephen
    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2010), 878 (13-14), 994-1002CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
    A rapid 2 min liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method operating in multiple reaction ion monitoring mode was developed and validated that allows for the characterization and simultaneous quantification of 11 phytoestrogen metabolites with mass transitions m/z 241/119 (equol), 253/132 (daidzein), 255/149 (dihydrodaidzein), 257/108 (O-desmethylangolesin), 269/133 (genistein), 283/184 (glycitein), 267/191 (formononetin), 289/109 (biochanin A), 267/91 (coumestrol), enterodiol (301/253), and enterolactone (297/253). The method was demonstrated to be specific and sensitive, and a linear response for each phytoestrogen was obsd. over a range of 1-5000 ng/mL in human serum with the exception of dihydrodaidzein, whose lower limit of quantification was 2 ng/mL. The sepn. was carried out on a Synergi Polar-RP 2.5 μ (50 mm × 2.0 mm i.d.) column at 50 °C with water and acetonitrile (both contg. 10 mM ammonium acetate) as the mobile phase under gradient conditions at a flow rate of 0.75 mL/min. This LC-MS/MS method is very useful for high-throughput anal. of phytoestrogens and proved to be simple, sensitive, reproducible, and reliable.
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  14. 14
    Vela-Soria, F.; Jiménez-Díaz, I.; Rodríguez-Gómez, R. Determination of benzophenones in human placental tissue samples by liquid chromatography–tandem mass spectrometry. Talanta 2011, 85, 1848– 1855,  DOI: 10.1016/j.talanta.2011.07.030
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    14
    Determination of benzophenones in human placental tissue samples by liquid chromatography-tandem mass spectrometry
    Vela-Soria, F.; Jimenez-Diaz, I.; Rodriguez-Gomez, R.; Zafra-Gomez, A.; Ballesteros, O.; Navalon, A.; Vilchez, J. L.; Fernandez, M. F.; Olea, N.
    Talanta (2011), 85 (4), 1848-1855CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
    Benzophenones (BPs) are a family of compds. widely used to protect the skin and hair from UV irradn. Despite human exposure to BPs through dermal application of products contg. sunscreen agents and the increasing evidence that BPs are able to interfere with endocrine systems, few studies have examd. the occurrence of BPs in humans. In this work, the authors propose a new liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method to det. 6 BPs, namely, benzophenone-1 (BP-1), benzophenone-2 (BP-2), benzophenone-3 (BP-3), benzophenone-6 (BP-6), benzophenone-8 (BP-8) and 4-hydroxybenzophenone (4-OH-BP) in human placental tissue samples. The method involves an extn. step of the analytes from the samples using Et acetate, followed by a clean-up step using centrifugation prior to their quantification by LC-MS/MS using an atm. pressure chem. ionization (APCI) interface in the pos. mode. Benzophenone-d10 (BP-d10) was used as surrogate. Found detection limits (LOD) ranged from 0.07 to 0.3 ng g-1 and quantification limits (LOQ) from 0.3 to 1.0 ng g-1, while inter- and intra-day variability was under 5%. The method was validated using std. addn. calibration and a recovery assay. Recovery rates for spiked samples ranged from 98 to 104%. This method was satisfactorily applied for the detn. of BPs in 16 placental tissue samples collected from women who live in Granada (Spain).
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  15. 15
    Azzouz, A.; Rascón, A. J.; Ballesteros, E. Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography–mass spectrometry. J. Pharm. Biomed. Anal. 2016, 119, 16– 26,  DOI: 10.1016/j.jpba.2015.11.024
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    15
    Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography-mass spectrometry
    Azzouz, Abdelmonaim; Rascon, Andres J.; Ballesteros, Evaristo
    Journal of Pharmaceutical and Biomedical Analysis (2016), 119 (), 16-26CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
    A highly sensitive gas chromatog.-mass spectrometry (GC-MS) method for the detn. of endocrine disrupting chems. (EDCs) including parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human breast milk, blood and urine samples is proposed. Blood and milk require a pretreatment to remove proteins and other substances potentially interfering with the continuous solid-phase extn. (SPE) system used; urine samples can be directly introduced into the system after filtering. Analytes are retained on a LiChrolut EN column and derivatized by silylation following elution with acetonitrile. The resulting trimethylsilyl derivs. are detd. by GC-MS. The proposed method exhibited good linearity (R2 >0.995) for all target EDCs over the concn. range 0.7-10,000 ng/l in urine, and 3.3-50,000 ng/l in blood and milk. Also, it provided low limits of detection (0.2-1.8 ng/l in urine, and 1.0-9.0 ng/l in blood and milk), good precision (relative std. deviations less than 7%) and recoveries from 86 to 104%. A total of 24 human fluid samples were analyzed and most found to contain some target EDC at concns. from 0.10 to 14 μg/l.
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  16. 16
    de Oliveira, M. L.; Rocha, B. A.; Souza, VCdO.; Barbosa, F. Determination of 17 potential endocrine-disrupting chemicals in human saliva by dispersive liquid-liquid microextraction and liquid chromatography-tandem mass spectrometry. Talanta 2019, 196, 271– 276,  DOI: 10.1016/j.talanta.2018.12.067
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    16
    Determination of 17 potential endocrine-disrupting chemicals in human saliva by dispersive liquid-liquid microextraction and liquid chromatography-tandem mass spectrometry
    de Oliveira Mariana Lepri; Rocha Bruno Alves; Souza Vanessa Cristina de Oliveira; Barbosa Fernando Jr
    Talanta (2019), 196 (), 271-276 ISSN:.
    Endocrine-disrupting chemicals are a group of emerging contaminants that alters the function of the endocrine system, causing possible adverse health effects. In this study, a dispersive liquid-liquid microextraction method coupled with liquid chromatography-mass spectrometry for the simultaneous determination of 17 potential EDCs, bisphenols (A, S, P, AP, AF, Z), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben), benzophenones (3, 1, 2, 8, 4-OH BP) and triclocarban, in human saliva samples was developed. Several parameters such as, type and volume of extraction and dispersive solvents, pH sample, ionic strength and, agitation, that affect extraction efficiency were investigated. Under the optimized conditions, the matrix-matched calibration curves of all analytes presented correlation coefficients higher than 0.99 (range level of 1-20 ng mL(-1)). The intra and inter-day coefficient of variation and relative standard deviation were lower than 20%, at 1 ng mL(-1). The limits of detection and quantification ranged from 0.01 to 0.15 ng mL(-1) and 0.05-0.40 ng mL(-1), respectively. Finally, the proposed method was applied in the simultaneous determination of several endocrine-disrupting chemicals classes in 10 human saliva samples In conclusion, the proposed method is an attractive alternative for application in large-scale human biomonitoring studies.
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  17. 17
    Kolatorova Sosvorova, L.; Chlupacova, T.; Vitku, J. Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS. Talanta 2017, 174, 21– 28,  DOI: 10.1016/j.talanta.2017.05.070
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    17
    Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS
    Kolatorova Sosvorova, Lucie; Chlupacova, Tereza; Vitku, Jana; Vlk, Martin; Heracek, Jiri; Starka, Luboslav; Saman, David; Simkova, Marketa; Hampl, Richard
    Talanta (2017), 174 (), 21-28CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
    In this study, a novel liq. chromatog. - tandem mass spectrometry method for the simultaneous detn. of bisphenols (BPA, BPS, BPF, BPAF), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben) and estrogens (estrone, estradiol, estriol) in human plasma is presented. Since all analytes possess the phenolic group, dansyl chloride derivatization was applied in order to gain high sensitivity. The method was validated according to FDA guidelines, and all validation requirements were satisfactory. The lower limits of quantifications were 41.6, 54.9, 43.5 and 150.8 pg/mL for BPA, BPS, BPF and BPAF; 172, 149, 171, 134 and 202 pg/mL for methyl-, ethyl-, propyl-, butyl- and benzyl-paraben; 10.5, 6.7 and 9.4 pg/mL for estrone, estradiol and estriol, resp. This is the first method allowing the detn. of plasma bisphenols, parabens and estrogens in one run, and also the first detn. of BPF levels in human plasma. The method was used to examine the plasma levels of healthy normospermic men, where three times higher plasma levels of BPF than BPA were found.
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  18. 18
    Braun, D.; Ezekiel, C. N.; Abia, W. A. Monitoring Early Life Mycotoxin Exposures via LC-MS/MS Breast Milk Analysis. Anal. Chem. 2018, 90, 14569– 14577,  DOI: 10.1021/acs.analchem.8b04576
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    18
    Monitoring Early Life Mycotoxin Exposures via LC-MS/MS Breast Milk Analysis
    Braun, Dominik; Ezekiel, Chibundu N.; Abia, Wilfred A.; Wisgrill, Lukas; Degen, Gisela H.; Turner, Paul C.; Marko, Doris; Warth, Benedikt
    Analytical Chemistry (Washington, DC, United States) (2018), 90 (24), 14569-14577CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    Infants are particularly susceptible toward the toxic effects of food contaminants, including mycotoxins. However, multimycotoxin exposure assessment in breast milk has received very limited attention so far, resulting in a poor understanding of coexposures during early life. Here, we present the development and application of a highly sensitive, specific, and quant. assay assessing up to 28 mycotoxins, including regulated (aflatoxins, ochratoxin A, deoxynivalenol, zearalenone) and emerging mycotoxins as well as key metabolites by LC-MS/MS. After careful optimization of the sample prepn. procedure, a QuEChERS protocol combined with a freeze-out step was validated inhouse. The limits of quantification varied between 0.009 and 2.9 ng/mL, and for most analytes extn. recovery (74-116%) and intermediate precision (2-20%) were satisfactory. The method was applied to examine multiple breast milk samples obtained from 22 women (n = 75 in total) from Ogun State, Nigeria. Most samples were either entirely free of mycotoxins or contaminated to a minimal extent with beauvericin (56%), enniatin B (9%), ochratoxin A (15%), and aflatoxin M1 (1%). The most abundant mycotoxin was beauvericin, which was not reported in this biol. fluid before, with concns. up to 0.019 ng/mL. In conclusion, the method demonstrated to be fit for purpose to det. and quantify low background contaminations in human breast milk. On the basis of the high sensitivity of the novel anal. method, it was possible to deduce that tolerable daily intake values were not exceeded by breastfeeding in the examd. infants.
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  19. 19
    Šarkanj, B.; Ezekiel, C. N.; Turner, P. C. Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers. Anal. Chim. Acta 2018, 1019, 84– 92,  DOI: 10.1016/j.aca.2018.02.036
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    19
    Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers
    Sarkanj, Bojan; Ezekiel, Chibundu N.; Turner, Paul C.; Abia, Wilfred A.; Rychlik, Michael; Krska, Rudolf; Sulyok, Michael; Warth, Benedikt
    Analytica Chimica Acta (2018), 1019 (), 84-92CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
    There is a crit. need to better understand the patterns, levels and combinatory effects of exposures the authors are facing through the authors' diet and environment. Mycotoxin mixts. are of particular concern due to chronic low dose exposures caused by naturally contaminated food. To facilitate new insights into their role in chronic disease, mycotoxins and their metabolites are quantified in bio-fluids as biomarkers of exposure. Here, the authors describe a highly sensitive urinary assay based on ultra-HPLC - tandem mass spectrometer (UHPLC-MS/MS) and 13C-labeled or deuterated internal stds. covering the most relevant regulated and emerging mycotoxins. Utilizing enzymic pre-treatment, solid phase extn. and UHPLC sepn., the sensitivity of the method was significantly higher (10-160x lower LODs) than in a previously described method used for comparison purpose, and stable isotopes provided compensation for challenging matrix effects. This method was inhouse validated and applied to re-assess mycotoxin exposure in urine samples obtained from Nigerian children, adolescent and adults, naturally exposed through their regular diet. Owing to the methods high sensitivity, biomarkers were detected in all samples. The mycoestrogen zearalenone was the most frequently detected contaminant (82%) but also ochratoxin A (76%), aflatoxin M1 (73%) and fumonisin B1 (71%) were quantified in a large share of urines. Overall, 57% of 120 urines were contaminated with both, aflatoxin M1 and fumonisin B1, and other co-exposures were frequent. These results clearly demonstrate the advanced performance of the method to assess lowest background exposures (pg mL-1 range) using a single, highly robust assay that will allow for the systematic investigation of low dose effects on human health.
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    Jamnik, T.; Flasch, M.; Braun, D. Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development. Nat. Commun. 2022, 13, 2653
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    20
    Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development
    Jamnik, Thomas; Flasch, Mira; Braun, Dominik; Fareed, Yasmin; Wasinger, Daniel; Seki, David; Berry, David; Berger, Angelika; Wisgrill, Lukas; Warth, Benedikt
    Nature Communications (2022), 13 (1), 2653CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
    Exposure to synthetic and natural chems. is a major environmental risk factor in the etiol. of many chronic diseases. Investigating complex co-exposures is necessary for a holistic assessment in exposome-wide assocn. studies. In this work, a sensitive liq. chromatog.-tandem mass spectrometry approach was developed and validated. The assay enables the anal. of more than 80 highly-diverse xenobiotics in urine, serum/plasma, and breast milk; with detection limits generally in the pg-ng mL-1 range. In plasma of extremely-premature infants, 27 xenobiotics are identified; including contamination with plasticizers, perfluorinated alkylated substances and parabens. In breast milk samples collected longitudinally over the first 211 days post-partum, 29 analytes are detected, including pyrrolizidine- and tropane alkaloids which have not been identified in this matrix before. A preliminary estn. of daily toxicant intake via breast milk is conducted. In conclusion, we observe significant early-life co-exposure to multiple toxicants, and demonstrate the method's applicability for large-scale exposomics-type cohort studies.
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  21. 21
    Marin, S.; Ramos, A. J.; Cano-Sancho, G.; Sanchis, V. Mycotoxins: Occurrence, toxicology, and exposure assessment. Food Chem. Toxicol. 2013, 60, 218– 237,  DOI: 10.1016/j.fct.2013.07.047
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    21
    Mycotoxins: Occurrence, toxicology, and exposure assessment
    Marin, S.; Ramos, A. J.; Cano-Sancho, G.; Sanchis, V.
    Food and Chemical Toxicology (2013), 60 (), 218-237CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
    A review. Mycotoxins are abiotic hazards produced by certain fungi that can grow on a variety of crops. Consequently, their prevalence in plant raw materials may be relatively high. The concn. of mycotoxins in finished products is usually lower than in raw materials. In this review, occurrence and toxicol. of the main mycotoxins are summarised. Furthermore, methodol. approaches for exposure assessment are described. Existing exposure assessments, both through contamination and consumption data and biomarkers of exposure, for the main mycotoxins are also discussed.
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  22. 22
    Xu, Z.; Liu, J.; Wu, X.; Huang, B.; Pan, X. Nonmonotonic responses to low doses of xenoestrogens: A review. Environ. Res. 2017, 155, 199– 207,  DOI: 10.1016/j.envres.2017.02.018
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    Nonmonotonic responses to low doses of xenoestrogens: A review
    Xu, Zhixiang; Liu, Jun; Wu, Xinhao; Huang, Bin; Pan, Xuejun
    Environmental Research (2017), 155 (), 199-207CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
    A review. Xenoestrogens (XEs) mimic or block the synthesis, metab. and transport of normal endogenous hormones, disturbing normal endocrine function. The available data on the nonmonotonic estrogenic effects of low doses of many XEs are reviewed, covering in vitro, in vivo and epidemiol. studies. The obsd. nonmonotonic patterns of the dose-response curves are discussed, along with possible underlying mechanisms. This review is intended to provide guidance for harm predication and to suggest prevention measures.
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    Christiansen, S.; Marta, A.; Julie, B.; Anne Marie, V.; Gitte Alsing, P.; Ulla, H. Low-dose effects of bisphenol A on early sexual development in male and female rats. Reproduction 2014, 147, 477– 487,  DOI: 10.1530/REP-13-0377
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    Low-dose effects of bisphenol a on early sexual development in male and female rats
    Christiansen, Sofie; Axelstad, Marta; Boberg, Julie; Vinggaard, Anne Marie; Pedersen, Gitte Alsing; Hass, Ulla
    Reproduction (Bristol, United Kingdom) (2014), 147 (4), 477-487CODEN: RCUKBS; ISSN:1470-1626. (Bioscientifica Ltd.)
    Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurol. development; however, it is controversial whether BPA has effects in the microgram per kg dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no obsd. adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kg dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (n = 22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ wts. in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kg dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.
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    Paterni, I.; Granchi, C.; Minutolo, F. Risks and benefits related to alimentary exposure to xenoestrogens. Crit. Rev. Food Sci. Nutr. 2017, 57, 3384– 3404,  DOI: 10.1080/10408398.2015.1126547
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    Risks and benefits related to alimentary exposure to xenoestrogens
    Paterni, Ilaria; Granchi, Carlotta; Minutolo, Filippo
    Critical Reviews in Food Science and Nutrition (2017), 57 (16), 3384-3404CODEN: CRFND6; ISSN:1040-8398. (Taylor & Francis, Inc.)
    Xenoestrogens are widely diffused in the environment and in food, thus a large portion of human population worldwide is exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks assocd. to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chems. possessing estrogenic activities, that are commonly defined as endocrine disrupting chems. (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review.
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    Chung, M. K.; Buck Louis, G. M.; Kannan, K.; Patel, C. J. Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes. Environ. Int. 2019, 125, 505– 514,  DOI: 10.1016/j.envint.2018.11.037
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    Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes
    Chung, Ming Kei; Buck Louis, Germaine M.; Kannan, Kurunthachalam; Patel, Chirag J.
    Environment International (2019), 125 (), 505-514CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    Exposome-wide assocn. studies (EWAS) are a systematic and unbiased way to investigate multiple environmental factors assocd. with phenotype. We applied EWAS to study semen quality and queried the sample size requirements to detect modest assocns. in a reproductive cohort. We conducted 1. a multivariate EWAS of 128 endocrine disrupting chems. (EDCs) from 15 chem. classes measured in urine/serum relative to 7 semen quality endpoints in a prospective cohort study comprising 473 men and 2. estd. the sample size requirements for EWAS etiol. investigations. None of the EDCs were assocd. with semen quality endpoints after adjusting for multiple tests. However, several EDCs (e.g., polychlorinated biphenyl congeners 99, 105, 114, and 167) were assocd. with raw p < 0.05. In a post hoc statistical power anal. with the obsd. effect sizes, we detd. that EWAS research in male fertility will require a mean sample size of 2696 men (1795-3625) to attain a power of 0.8. The av. size of four published studies is 201 men. Existing cohort studies with hundreds of participants are underpowered (<0.8) for EWAS-related investigations. Merging cohorts to ensure a sufficient sample size can facilitate the use of EWAS methods for assessing EDC mixts. that impact semen quality.
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    Rampler, E.; Abiead, Y. E.; Schoeny, H. Recurrent Topics in Mass Spectrometry-Based Metabolomics and Lipidomics─Standardization, Coverage, and Throughput. Anal. Chem. 2021, 93, 519– 545,  DOI: 10.1021/acs.analchem.0c04698
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    Recurrent Topics in Mass Spectrometry-Based Metabolomics and Lipidomics-Standardization, Coverage, and Throughput
    Rampler, Evelyn; El Abiead, Yasin; Schoeny, Harald; Rusz, Mate; Hildebrand, Felina; Fitz, Veronika; Koellensperger, Gunda
    Analytical Chemistry (Washington, DC, United States) (2021), 93 (1), 519-545CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
    There is no expanded citation for this reference.
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    Liu, X.; Zhou, L.; Shi, X.; Xu, G. New advances in analytical methods for mass spectrometry-based large-scale metabolomics study. TrAC, Trends Anal. Chem. 2019, 121, 115665  DOI: 10.1016/j.trac.2019.115665
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    New advances in analytical methods for mass spectrometry-based large-scale metabolomics study
    Liu, Xinyu; Zhou, Lina; Shi, Xianzhe; Xu, Guowang
    TrAC, Trends in Analytical Chemistry (2019), 121 (), 115665CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B.V.)
    A Review. Large-scale metabolomics study based on large population cohorts is increasingly applied to identify important metabolites or crit. metabolic alterations related to the metabolite perturbation in disease states or under interventions and to investigate metabolic difference and stimuli response in genetically different individuals. Mass spectrometry (MS) coupled with different chromatog. methods, is suitable for large-scale metabolomics study due to its high sensitivity and selectivity, wide dynamic range, and rich information. However, there are still a series of challenges for really realizing large-scale metabolomics applications. Hence, in this review, we mainly focused on new advances in sample pretreatment methods, nontargeted, targeted and pseudotargeted metabolic data collection techniques, and data correction methods used for MS-based large-scale metabolomics study. Typical applications of MS-based large-scale metabolomics methods in mol. epidemiol., precision medicine, and genome-wide assocn. studies with metabolomics (mGWAS) are also given.
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    Schwaiger, M.; Schoeny, H.; El Abiead, Y.; Hermann, G.; Rampler, E.; Koellensperger, G. Merging metabolomics and lipidomics into one analytical run. Analyst 2019, 144, 220– 229,  DOI: 10.1039/C8AN01219A
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    Merging metabolomics and lipidomics into one analytical run
    Schwaiger, Michaela; Schoeny, Harald; El Abiead, Yasin; Hermann, Gerrit; Rampler, Evelyn; Koellensperger, Gunda
    Analyst (Cambridge, United Kingdom) (2019), 144 (1), 220-229CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
    A novel integrated metabolomics/lipidomics workflow is introduced enabling high coverage of polar metabolites and non-polar lipids within one anal. run. Dual HILIC and RP chromatog. were combined to high-resoln. mass spectrometry. As a major advantage, only one data file per sample was obtained by fully automated simultaneous anal. of two exts. per sample. Hence, the unprecedented high coverage without compromise on anal. throughput was not only obtained by the orthogonality of the chromatog. sepns., but also by the implementation of dedicated sample prepn. procedures resulting in optimum extn. efficiency for both sub-omes. Thus, the method addressed completely hydrophilic sugars and org. acids next to water-insol. triglycerides. As for the timing of the dual chromatog. setup, HILIC and RP sepn. were performed consecutively. However, re-equilibration of the HILIC column during elution of RP compds. and vice versa reduced the overall anal. time by one third to 32 min. Application to the Std. Ref. Material SRM 1950 - Metabolites in Frozen Human Plasma resulted in >100 metabolite and >380 lipid identifications based on accurate mass implementing fast polarity switching and acquiring data dependent MS2 spectra with the use of automated exclusion lists. Targeted quantification based on external calibrations and 13C labeled yeast internal stds. was successfully accomplished for 59 metabolites. Moreover, the potential for lipid quantification was shown integrating non-endogenous lipids as internal stds. In human plasma, concns. ranging over 4 orders of magnitude (low nM to high μM) were assessed.
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    Fitz, V.; El Abiead, Y.; Berger, D.; Koellensperger, G. Systematic Investigation of LC Miniaturization to Increase Sensitivity in Wide-Target LC-MS-Based Trace Bioanalysis of Small Molecules. Front. Mol. Biosci. 2022, 9, 857505  DOI: 10.3389/fmolb.2022.857505
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    Systematic investigation of LC miniaturization to increase sensitivity in wide-target LC-MS-based trace bioanalysis of small molecules
    Fitz, Veronika; El Abiead, Yasin; Berger, Daniel; Koellensperger, Gunda
    Frontiers in Molecular Biosciences (2022), 9 (), 857505CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)
    Covering a wide spectrum of mols. is essential for global metabolome assessment. While metabolomics assays are most frequently carried out in microbore LC-MS anal., reducing the size of the anal. platform has proven its ability to boost sensitivity for specific -omics applications. In this study, we elaborate the impact of LC miniaturization on exploratory smallmol. LC-MS anal., focusing on chromatog. properties with crit. impact on peak picking and statistical anal. We have assessed a panel of small mols. comprising endogenous metabolites and environmental contaminants covering three flow regimes-anal., micro-, and nano-flow. Miniaturization to the micro-flow regime yields moderately increased sensitivity as compared to the nano setup, where median sensitivity gains around 80-fold are obsd. in protein-pptd. blood plasma ext. This gain resulting in higher coverage at low μg/L concns. is compd. dependent. At the same time, the nano-LC-high-resoln. mass spectrometry (HRMS) approach reduces the investigated chem. space as a consequence of the trap-and-elute nano-LC platform. Finally, while all three setups show excellent retention time stabilities, rapid gradients jeopardize the peak area repeatability of the nano-LC setup. Micro-LC offers the best compromise between improving signal intensity and metabolome coverage, despite the fact that only incremental gains can be achieved. Hence, we recommend using micro-LC for wide-target small-mol. trace bioanal. and global metabolomics of abundant samples.
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    Bloszies, C. S.; Fiehn, O. Using untargeted metabolomics for detecting exposome compounds. Curr. Opin. Toxicol. 2018, 8, 87– 92,  DOI: 10.1016/j.cotox.2018.03.002
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    Oesterle, I.; Braun, D.; Rompel, A.; Warth, B. Quantifying up to 90 polyphenols simultaneously in human bio-fluids by LC-MS/MS. Anal. Chim. Acta 2022, 1216, 339977,  DOI: 10.1016/j.aca.2022.339977
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    Quantifying up to 90 polyphenols simultaneously in human bio-fluids by LC-MS/MS
    Oesterle, Ian; Braun, Dominik; Rompel, Annette; Warth, Benedikt
    Analytica Chimica Acta (2022), 1216 (), 339977CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
    Establishing a method for human biomonitoring (HBM) of polyphenols enables the assessment of internal concns. of these food bio-actives and the correlation with potential health effects such as antioxidant or anti-inflammatory properties. Thus, a targeted LC-MS/MS method for quantifying up to 90 analytes, representing the main polyphenol classes including flavanones, isoflavones, stilbenes, and phenolic acids, was developed for human urine, serum, and plasma. The method was established for low sample vols. and with a cost and time efficient sample prepn. protocol for high-throughput, which is crit. for its application in large cohort and exposome-wide assocn. studies. On av., the sample prepn. yielded extn. efficiencies of 98% for urine, 98% for serum, and 87% for plasma. Limits of detection were between 0.11 ng mL-1 and 300 ng mL-1 for urine, 0.12 ng mL-1 and 190 ng mL-1 for serum, and 0.12 ng mL-1 and 340 ng mL-1 for plasma, excluding one analyte. Inhouse validation revealed that 66, 49, and 64 analytes for urine, serum, and plasma, resp., fulfilled all stringent requirements, that are usually utilized for tailored single analyte methods, at all evaluated concn. levels. After validation, this method was applied in a proof-of-principle study that detected 39 polyphenols in urine. Changes in the concns. of the analytes after the ingestion of a high polyphenol smoothie was examd. over 24 h. The study further confirmed that the majority of polyphenols detected were phenolic acids, and phase II conjugated metabolites were more abundant than their resp. non-conjugated forms.
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    Braun, D.; Abia, W. A.; Šarkanj, B. Mycotoxin-mixture assessment in mother-infant pairs in Nigeria: From mothers’ meal to infants’ urine. Chemosphere 2022, 287, 132226  DOI: 10.1016/j.chemosphere.2021.132226
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    Mycotoxin-mixture assessment in mother-infant pairs in Nigeria: From mothers' meal to infants'urine
    Braun, Dominik; Abia, Wilfred A.; Sarkanj, Bojan; Sulyok, Michael; Waldhoer, Thomas; Erber, Astrid C.; Krska, Rudolf; Turner, Paul C.; Marko, Doris; Ezekiel, Chibundu N.; Warth, Benedikt
    Chemosphere (2022), 287 (Part_2), 132226CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
    Exposure to food and environmental contaminants is a global environmental health issue. In this study, innovative LC-MS/MS approaches were applied to investigate mycotoxin co-exposure in mother-infant pairs (n = 23) by analyzing matched plate-ready food, breast milk and urine samples of mothers and their exclusively breastfed infants. The study revealed frequent co-occurrence of two to five mycotoxins. Regulated (e.g. aflatoxins, deoxynivalenol and ochratoxin A) and emerging mycotoxins (e.g. alternariol monomethyl ether and beauvericin) were frequently detected (3%-89% and 45%-100%), in at least one specimen. In addn., a moderate assocn. of ochratoxin A in milk to urine of mothers (r = 0.47; p = 0.003) and infants (r = 0.52; p = 0.019) but no other significant correlations were found. Av. concn. levels in food mostly did not exceed European max. residue limits, and intake ests. demonstrated exposure below tolerable daily intake values. Infants were exposed to significantly lower toxin levels compared to their mothers, indicating the protective effect of breastfeeding. However, the transfer into milk and urine and the resulting chronic low-dose exposure warrant further monitoring. In the future, occurrence of mycotoxin-mixts., and their combined toxicol. effects need to be comprehensively considered and implemented in risk management strategies. These should aim to minimize early-life exposure in crit. developmental stages.
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    Narduzzi, L.; Royer, A.-L.; Bichon, E. Ammonium Fluoride as Suitable Additive for HILIC-Based LC-HRMS Metabolomics. Metabolites 2019, 9, 292  DOI: 10.3390/metabo9120292
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    Ammonium fluoride as suitable additive for HILIC-based LC-HRMS metabolomics
    Narduzzi, Luca; Royer, Anne-Lise; Bichon, Emmanuelle; Guitton, Yann; Buisson, Corinne; Le Bizec, Bruno; Dervilly-Pinel, Gaud
    Metabolites (2019), 9 (12), 292CODEN: METALU; ISSN:2218-1989. (MDPI AG)
    Hydrophilic Interaction Liq. Chromatog. (HILIC) chromatog. is widely applied in metabolomics as a complementary strategy to reverse phase chromatog. Nevertheless, it still faces several issues in terms of peak shape and compds. ionization, limiting the automatic de-convolution and data semi-quantification performed through dedicated software. A way to improve the chromatog. and ionization performance of a HILIC method is to modify the electrostatic interactions of the analytes with both mobile and stationary phases. In this study, using a ZIC-HILIC chromatog. phase, we evaluated the performance of ammonium fluoride (AF) as additive salt, comparing its performance to ammonium acetate (AA). Three comparative criteria were selected: (1) identification and peak quality of 34 stds. following a metabolomics-specific evaluation approach, (2) an intraday repeatability test with real samples and (3) performing two real metabolomics fingerprints with the AF method to evaluate its inter-day repeatability. The AF method showed not only higher ionization efficiency and signal-to-noise ratio but also better repeatability and robustness than the AA approach. A tips and tricks section is then added, aiming at improving method replicability for further users. In conclusion, ammonium fluoride as additive salt presents several advantages and might be considered as a step forward in the application of robust HILIC methods in metabolomics.
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    Galvez, L.; Rusz, M.; Schwaiger-Haber, M. Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics. Metallomics 2019, 11, 1716– 1728,  DOI: 10.1039/c9mt00141g
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    Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics
    Galvez, Luis; Rusz, Mate; Schwaiger-Haber, Michaela; El Abiead, Yasin; Hermann, Gerrit; Jungwirth, Ute; Berger, Walter; Keppler, Bernhard K.; Jakupec, Michael A.; Koellensperger, Gunda
    Metallomics (2019), 11 (10), 1716-1728CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
    In this work we introduce a novel -omics workflow enabling the parallel study of platinum drug uptake and its distribution between nucleus/protein and small mol. fraction along with metabolic changes after different treatment time points. This integrated metallomics/metabolomics approach is facilitated by a tailored sample prepn. workflow suitable for preclin. studies on adherent cancer cell models. Inductively coupled plasma mass spectrometry monitors the platinum drug, while the metabolomics tool-set is provided by hydrophilic interaction liq. chromatog. combined with high-resoln. Orbitrap mass spectrometry. The implemented method covers biochem. key pathways of cancer cell metab. as shown by a panel of >130 metabolite stds. Furthermore, the addn. of yeast-based 13C-enriched internal stds. upon extn. enabled a novel targeted/untargeted anal. strategy. In this study we used our method to compare an oxaliplatin sensitive human colon cancer cell line (HCT116) and its corresponding resistant model. In the acquired oxaliplatin resistant cells distinct differences in oxaliplatin accumulation correlated with differences in metabolomic rearrangements. Using this multi-omics approach for platinum-treated samples facilitates the generation of novel hypotheses regarding the susceptibility and resistance towards oxaliplatin.
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    Koelmel, J. P.; Kroeger, N. M.; Gill, E. L. Expanding lipidome coverage using LC-MS/MS data-dependent acquisition with automated exclusion list generation. J. Am. Soc. Mass Spectrom. 2017, 28, 908– 917,  DOI: 10.1007/s13361-017-1608-0
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    Expanding Lipidome Coverage Using LC-MS/MS Data-Dependent Acquisition with Automated Exclusion List Generation
    Koelmel, Jeremy P.; Kroeger, Nicholas M.; Gill, Emily L.; Ulmer, Candice Z.; Bowden, John A.; Patterson, Rainey E.; Yost, Richard A.; Garrett, Timothy J.
    Journal of the American Society for Mass Spectrometry (2017), 28 (5), 908-917CODEN: JAMSEF; ISSN:1044-0305. (Springer)
    Untargeted omics analyses aim to comprehensively characterize biomols. within a biol. system. Changes in the presence or quantity of these biomols. can indicate important biol. perturbations, such as those caused by disease. With current technol. advancements, the entire genome can now be sequenced; however, in the burgeoning fields of lipidomics, only a subset of lipids can be identified. The recent emergence of high resoln. tandem mass spectrometry (HR-MS/MS), in combination with ultra-high performance liq. chromatog., has resulted in an increased coverage of the lipidome. Nevertheless, identifications from MS/MS are generally limited by the no. of precursors that can be selected for fragmentation during chromatog. elution. Therefore, we developed the software IE-Omics to automate iterative exclusion (IE), where selected precursors using data-dependent topN analyses are excluded in sequential injections. In each sequential injection, unique precursors are fragmented until HR-MS/MS spectra of all ions above a user-defined intensity threshold are acquired. IE-Omics was applied to lipidomics analyses in Red Cross plasma and substantia nigra tissue. Coverage of the lipidome was drastically improved using IE. When applying IE-Omics to Red Cross plasma and substantia nigra lipid exts. in pos. ion mode, 69% and 40% more mol. identifications were obtained, resp. In addn., applying IE-Omics to a lipidomics workflow increased the coverage of trace species, including odd-chained and short-chained diacylglycerides and oxidized lipid species. By increasing the coverage of the lipidome, applying IE to a lipidomics workflow increases the probability of finding biomarkers and provides addnl. information for detg. etiol. of disease.
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    MacLean, B.; Tomazela, D. M.; Shulman, N. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 2010, 26, 966– 968,  DOI: 10.1093/bioinformatics/btq054
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    Skyline: an open source document editor for creating and analyzing targeted proteomics experiments
    MacLean, Brendan; Tomazela, Daniela M.; Shulman, Nicholas; Chambers, Matthew; Finney, Gregory L.; Frewen, Barbara; Kern, Randall; Tabb, David L.; Liebler, Daniel C.; MacCoss, Michael J.
    Bioinformatics (2010), 26 (7), 966-968CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
    Summary: Skyline is a Windows client application for targeted proteomics method creation and quant. data anal. It is open source and freely available for academic and com. use. The Skyline user interface simplifies the development of mass spectrometer methods and the anal. of data from targeted proteomics expts. performed using selected reaction monitoring (SRM). Skyline supports using and creating MS/MS spectral libraries from a wide variety of sources to choose SRM filters and verify results based on previously obsd. ion trap data. Skyline exports transition lists to and imports the native output files from Agilent, Applied Biosystems, Thermo Fisher Scientific and Waters triple quadrupole instruments, seamlessly connecting mass spectrometer output back to the exptl. design document. The fast and compact Skyline file format is easily shared, even for expts. requiring many sample injections. A rich array of graphs displays results and provides powerful tools for inspecting data integrity as data are acquired, helping instrument operators to identify problems early. The Skyline dynamic report designer exports tabular data from the Skyline document model for in-depth anal. with common statistical tools. Availability: Single-click, self-updating web installation is available at http://proteome.gs.washington.edu/software/skyline. This web site also provides access to instructional videos, a support board, an issues list and a link to the source code project.
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    Ellison, SLR.; William, A. EURACHEM/CITAC Guide CG 4-Quantifying Uncertainty in Analytical Measurement, 3rd ed.; 2012.
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    Wei, T.; Simko, V. R package ″corrplot″: Visualization of a Correlation Matrix. 2017, https://githubcom/taiyun/corrplot (accessed April 11, 2022).
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    Pang, Z.; Chong, J.; Zhou, G.; de Lima Morais, D. A.; Chang, L.; Barrette, M.; Gauthier, C.; Jacques, P.-E.; Li, S.; Xia, J. MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 2021, 49, W388– W396,  DOI: 10.1093/nar/gkab382
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    MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights
    Pang, Zhiqiang; Chong, Jasmine; Zhou, Guangyan; Anderson de Lima Morais, David; Chang, Le; Barrette, Michel; Gauthier, Carol; Jacques, Pierre-Etienne; Li, Shuzhao; Xia, Jianguo
    Nucleic Acids Research (2021), 49 (W1), W388-W396CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    Since its first release over a decade ago, the MetaboAnalyst web-based platform has become widely used for comprehensive metabolomics data anal. and interpretation. Here we introduce MetaboAnalyst version 5.0, aiming to narrow the gap from raw data to functional insights for global metabolomics based on high-resoln. mass spectrometry (HRMS). Three modules have been developed to help achieve this goal, including: (i) a LC-MS Spectra Processing module which offers an easy-to-use pipeline that can perform automated parameter optimization and resumable anal. to significantly lower the barriers to LC-MS1 spectra processing; (ii) a Functional Anal. module which expands the previous MS Peaks to Pathways module to allow users to intuitively select any peak groups of interest and evaluate their enrichment of potential functions as defined by metabolic pathways and metabolite sets; (iii) a Functional Meta-Anal. module to combine multiple global metabolomics datasets obtained under complementary conditions or from similar studies to arrive at comprehensive functional insights. There are many other new functions including weighted joint-pathway anal., data-driven network anal., batch effect correction, merging tech. replicates, improved compd. name matching, etc. The web interface, graphics and underlying codebase have also been refactored to improve performance and user experience. At the end of an anal. session, users can now easily switch to other compatible modules for a more streamlined data anal.
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    Helmus, R.; ter Laak, T. L.; van Wezel, A. P.; de Voogt, P.; Schymanski, E. L. patRoon: open source software platform for environmental mass spectrometry based non-target screening. J. Cheminf. 2021, 13, 1  DOI: 10.1186/s13321-020-00477-w
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    patRoon: open source software platform for environmental mass spectrometry based non-target screening
    Helmus, Rick; ter Laak, Thomas L.; van Wezel, Annemarie P.; de Voogt, Pim; Schymanski, Emma L.
    Journal of Cheminformatics (2021), 13 (1), 1CODEN: JCOHB3; ISSN:1758-2946. (SpringerOpen)
    Abstr.: Mass spectrometry based non-target anal. is increasingly adopted in environmental sciences to screen and identify numerous chems. simultaneously in highly complex samples. However, current data processing software either lack functionality for environmental sciences, solve only part of the workflow, are not openly available and/or are restricted in input data formats. In this paper we present patRoon, a new R based open-source software platform, which provides comprehensive, fully tailored and straightforward non-target anal. workflows. In addn., patRoon offers various functionality and strategies to simplify and perform automated processing of complex (environmental) data effectively. patRoon implements several effective optimization strategies to significantly reduce computational times. The ability of patRoon to perform time-efficient and automated non-target data annotation of environmental samples is demonstrated with a simple and reproducible workflow using open-access data of spiked samples from a drinking water treatment plant study. In addn., the ability to easily use, combine and evaluate different algorithms was demonstrated for three commonly used feature finding algorithms. This article, combined with already published works, demonstrate that patRoon helps make comprehensive (environmental) non-target anal. readily accessible to a wider community of researchers.
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    Chambers, M. C.; Maclean, B.; Burke, R. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 2012, 30, 918– 920,  DOI: 10.1038/nbt.2377
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    A cross-platform toolkit for mass spectrometry and proteomics
    Chambers, Matthew C.; MacLean, Brendan; Burke, Robert; Amodei, Dario; Ruderman, Daniel L.; Neumann, Steffen; Gatto, Laurent; Fischer, Bernd; Pratt, Brian; Egertson, Jarrett; Hoff, Katherine; Kessner, Darren; Tasman, Natalie; Shulman, Nicholas; Frewen, Barbara; Baker, Tahmina A.; Brusniak, Mi-Youn; Paulse, Christopher; Creasy, David; Flashner, Lisa; Kani, Kian; Moulding, Chris; Seymour, Sean L.; Nuwaysir, Lydia M.; Lefebvre, Brent; Kuhlmann, Frank; Roark, Joe; Rainer, Paape; Detlev, Suckau; Hemenway, Tina; Huhmer, Andreas; Langridge, James; Connolly, Brian; Chadick, Trey; Holly, Krisztina; Eckels, Josh; Deutsch, Eric W.; Moritz, Robert L.; Katz, Jonathan E.; Agus, David B.; MacCoss, Michael; Tabb, David L.; Mallick, Parag
    Nature Biotechnology (2012), 30 (10), 918-920CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    Mass spectrometry-based proteomics has become an important component of biol. research. There have been several calls for improvements and standardization of proteomics data anal. frameworks, as well as for an application programming interface for proteomics data access. In response, ProteoWizard Toolkit was developed, a robust set of opensource, software libraries and applications designed to facilitate proteomics research. With version 3.0 of the ProteoWizard Toolkit8, the challenges in the field can be mitigated through open-source, permissively licensed, cross-platform software. The Toolkit has two components: first, a suite of libraries that facilitate the development and comparison of tools for proteomics data anal. and second, a set of tools, developed using these libraries, that performs a wide array of common proteomics analyses. ProteoWizard is built upon a modular framework of many independent libraries grouped in dependency levels.
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    Sobus, J. R.; Grossman, J. N.; Chao, A. Using prepared mixtures of ToxCast chemicals to evaluate non-targeted analysis (NTA) method performance. Anal. Bioanal. Chem. 2019, 411, 835– 851,  DOI: 10.1007/s00216-018-1526-4
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    Using prepared mixtures of ToxCast chemicals to evaluate non-targeted analysis (NTA) method performance
    Sobus, Jon R.; Grossman, Jarod N.; Chao, Alex; Singh, Randolph; Williams, Antony J.; Grulke, Christopher M.; Richard, Ann M.; Newton, Seth R.; McEachran, Andrew D.; Ulrich, Elin M.
    Analytical and Bioanalytical Chemistry (2019), 411 (4), 835-851CODEN: ABCNBP; ISSN:1618-2642. (Springer)
    Non-targeted anal. (NTA) methods are increasingly used to discover contaminants of emerging concern (CECs), but the extent to which these methods can support exposure and health studies remains to be detd.1416711539. EPA's Non-Targeted Anal. Collaborative Trial (ENTACT) was launched in 2016 to address this need. As part of ENTACT, 1269 unique substances from EPA's ToxCast library were combined to make ten synthetic mixts., with each mixt. contg. between 95 and 365 substances. As a participant in the trial, the authors first performed blinded NTA on each mixt. using liq. chromatog. (LC) coupled with high-resoln. mass spectrometry (HRMS). The authors then performed an unblinded evaluation to identify limitations of the authors' NTA method. Overall, at least 60% of spiked substances could be obsd. using selected methods. Discounting spiked isomers, true pos. rates from the blinded and unblinded analyses reached a max. of 46% and 65%, resp. An overall reproducibility rate of 75% was obsd. for substances spiked into more than one mixt. and obsd. at least once. Considerable discordance in substance identification was obsd. when comparing a subset of the authors' results derived from two sep. reversed-phase chromatog. methods. The authors conclude that a single NTA method, even when optimized, can likely characterize only a subset of ToxCast substances (and, by extension, other CECs). Rigorous quality control and self-evaluation practices should be required of labs generating NTA data to support exposure and health studies. Accurate and transparent communication of performance results will best enable meaningful interpretations and defensible use of NTA data. [Figure not available: see fulltext.].
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    Schymanski, E. L.; Jeon, J.; Gulde, R. Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence. Environ. Sci. Technol. 2014, 48, 2097– 2098,  DOI: 10.1021/es5002105
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    Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence
    Schymanski, Emma L.; Jeon, Junho; Gulde, Rebekka; Fenner, Kathrin; Ruff, Matthias; Singer, Heinz P.; Hollender, Juliane
    Environmental Science & Technology (2014), 48 (4), 2097-2098CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
    A method and framework for describing the identification of small mols. by high resoln. mass spectrometry (HRMS) is presented. A 5 level classification scheme was developed to indicate the proposed identification confidence levels in HRMS. The levels are confirmed structure, probable structure, substance class, unequivocal mol. formula, and exact mass of interest.
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    Karthikraj, R.; Lee, S.; Kannan, K. Biomonitoring of exposure to bisphenols, benzophenones, triclosan, and triclocarban in pet dogs and cats. Environ. Res. 2020, 180, 108821  DOI: 10.1016/j.envres.2019.108821
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    42
    Biomonitoring of exposure to bisphenols, benzophenones, triclosan, and triclocarban in pet dogs and cats
    Karthikraj, Rajendiran; Lee, Sunmi; Kannan, Kurunthachalam
    Environmental Research (2020), 180 (), 108821CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
    Similar to humans, pet animals are exposed to environmental contaminants through multiple sources and pathways. Although a few studies have demonstrated exposure of cats and dogs to environmental chems., little is known about exposure to bisphenols, benzophenone UV filters, and antibacterial agents. In this study, we measured three bisphenols, three benzophenone-type UV filters, triclosan (TCS), and triclocarban (TCC) in dog (n = 50) and cat urine (n = 50) collected from New York State, USA. Among bisphenols, BPS was found at the highest concns. (mean ± SD: 3.2 ± 8.5 ng/mL in dogs and 8.85 ± 30.0 ng/mL in cats) with detection frequencies of 96% in dogs and 78% in cats. Among benzophenones, BP-3 (oxybenzone) was the dominant compd. in pet urine, followed by BP-1 and BP-8. TCS was found at concns. higher than those of TCC in both cat and dog urine. There were no significant differences in bisphenol concns. between sexes or age groups, both in dogs and cats. The calcd. hazard quotients (HQ) suggested that the current exposure levels of BPS and BP-3 in pets were 2-5 orders of magnitude below the tentative threshold values available for humans.
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    Zhu, H.; Chinthakindi, S.; Kannan, K. A method for the analysis of 121 multi-class environmental chemicals in urine by high-performance liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2021, 1646, 462146  DOI: 10.1016/j.chroma.2021.462146
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    A method for the analysis of 121 multi-class environmental chemicals in urine by high-performance liquid chromatography-tandem mass spectrometry
    Zhu, Hongkai; Chinthakindi, Sridhar; Kannan, Kurunthachalam
    Journal of Chromatography A (2021), 1646 (), 462146CODEN: JCRAEY; ISSN:0021-9673. (Elsevier B.V.)
    Biomonitoring of human exposure to environmental chems. has gained momentum in recent years. Biomonitoring methods often include anal. of a single class of chems. with similar chem. properties. In this study, we describe a method that involves solid-phase extn. (SPE) coupled with liq. chromatog.-tandem mass spectrometry (LC-MS/MS) and capable of measuring 121 environmental chems. comprising plasticizers (PMs; n = 45), environmental phenols (EPs; n = 45), and pesticides (n = 31) through a single extn. of urine. Urine samples were incubated with 20 μL of β-glucuronidase/arylsulfatase (4000 units/mL urine) (from Helix pomatia) buffered at pH 5.5 for 2 h at 37 °C for optimal deconjugation conditions. We compared two extn. methods, namely liq.-liq. extn. and SPE, and the latter with ABS Elut NEXUS cartridges was optimized to yield best extn. efficiencies. For increased resoln. and chromatog. sepn., two methods involving Ultra AQ C18 and Betasil C18 columns were used. The MS/MS analyses were performed under both neg. and pos. ionization modes. The optimized method yielded excellent intra- and inter-day variabilities (relative std. deviation: 0.40-11%) and satisfactory recoveries (80-120%) for >95% of the analytes. The limits of detection were ≤ 0.1 ng/mL for 101 analytes and between 0.1 and 1.0 ng/mL for 18 analytes. The optimized SPE LC-MS/MS method was validated through the anal. of std. ref. materials and proficiency test urine samples and further applied in the anal. of 21 real urine samples to demonstrate simultaneous detn. of 121 environmental chems. in urine samples.
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    Jiang, C.; Wang, X.; Li, X. Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring. Cell 2018, 175, 277– 291,  DOI: 10.1016/j.cell.2018.08.060
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    Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring
    Jiang, Chao; Wang, Xin; Li, Xiyan; Inlora, Jingga; Wang, Ting; Liu, Qing; Snyder, Michael
    Cell (Cambridge, MA, United States) (2018), 175 (1), 277-291.e31CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biol. and chem. exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geog. locations. We found that individuals are potentially exposed to thousands of pan-domain species and chem. compds., including insecticides and carcinogens. Personal biol. and chem. exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geog. region. Integrated anal. of biol. and chem. exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.
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    Ougier, E.; Zeman, F.; Antignac, J.-P. Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A. Environ. Int. 2021, 154, 106563  DOI: 10.1016/j.envint.2021.106563
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    Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A
    Ougier, Eva; Zeman, Florence; Antignac, Jean-Philippe; Rousselle, Christophe; Lange, Rosa; Kolossa-Gehring, Marike; Apel, Petra
    Environment International (2021), 154 (), 106563CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    A review. The "European Human Biomonitoring Initiative" (HBM4EU) derives human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) and/or for occupationally exposed adults (HBM-GVWorker) for several priority substances and substance groups as identified by policy makers, scientists and stakeholders at EU and national level, including bisphenol A (BPA). Human exposure to BPA is widespread and of particular concern because of its known endocrine-disrupting properties. Unlike the conjugated forms of BPA circulating in the body, free BPA is known to interact with the nuclear estrogen receptors. Because free BPA is considered to be more toxicol. active than the conjugated forms (e.g. BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S)), its measurement in blood provides the superior surrogate of the biol. ED. However, considering the difficulty of implementing blood sampling in large HBM cohorts, as well as the current anal. capacities complying with the quality assurance (QA)/quality control (QC) schemes, total BPA in urine (i.e. the sum of free and conjugated forms of BPA measured after an hydrolysis of phase II metabolites) was retained as the relevant exposure biomarker for BPA. HBM-GVGenPop for total BPA in urine of 230μg/L and 135μg/L for adults and children, resp., were developed on the basis of toxicol. data. To derive these values, the concns. of urinary total BPA consistent with a steady-state exposure to the temporary Tolerable Daily Intake (t-TDI) of 4μg/kg bw/day set in 2015 by the European Food Safety Authority (EFSA) were estd. The BPA human physiol.-based pharmacokinetic (PBPK) model developed by Karrer et al. (2018) was used, assuming an oral exposure to BPA at the t-TDI level averaged over 24 h. Dermal uptake of BPA is suspected to contribute substantially to the total BPA body burden, which in comparison with the oral route, is generating a higher ratio of free BPA to total BPA in blood. Therefore, an alternative approach for calcg. the HBM-GVGenPop according to the estd. relative contributions of both the oral and dermal routes to the global BPA exposure is also discussed. Regarding BPA exposure at the workplace, the steady-state concn. of urinary total BPA was estd. after a dermal uptake of BPA that would generate the same concn. of free BPA in plasma (considered as the bioactive form) as would a 24 h-averaged intake to the European Chems. Agency (ECHA)'s oral DNEL of 8μg BPA/kg bw/day set for workers. The predicted concn. of urinary total BPA at steady-state is equiv. to, or exceeds the 95th percentile of total BPA in urine measured in different European HBM studies conducted in the general population. Thus, no HBM-GVWorker was proposed, as the high background level of BPA coming from environmental exposure - mostly through food intake - is making the discrimination with the occupational exposure to BPA difficult.
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    Wenzel, A. G.; Brock, J. W.; Cruze, L. Prevalence and predictors of phthalate exposure in pregnant women in Charleston, SC. Chemosphere 2018, 193, 394– 402,  DOI: 10.1016/j.chemosphere.2017.11.019
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    Prevalence and predictors of phthalate exposure in pregnant women in Charleston, SC
    Wenzel, Abby G.; Brock, John W.; Cruze, Lori; Newman, Roger B.; Unal, Elizabeth R.; Wolf, Bethany J.; Somerville, Stephen E.; Kucklick, John R.
    Chemosphere (2018), 193 (), 394-402CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
    Phthalates are plasticizers commonly detected in human urine due to widespread exposure from PVC plastics, food packaging, and personal care products. We sampled urine from 378 pregnant women during the second trimester of gestation living in Charleston, SC, and measured eight urinary phthalate metabolites as biomarkers of phthalate exposure: monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), and monomethyl phthalate (MMP). Demog. data was collected from questionnaires administered at the time of specimen collection. On av., concns. were highest for MEP (median = 47.0 ng/mL) and lowest for MMP (median = 1.92 ng/mL). Sociodemog. characteristics assocd. with elevated phthalate concns. included being unmarried, less educated, having a low income, high body mass index (BMI), and/or being African American. After racial stratification, age, BMI, education, and income were significantly assocd. with phthalate concns. in African American women. Marital status was assocd. with phthalate concns. in Caucasian women only, with greater concns. of MBP, MEHHP, MiBP, and MMP in unmarried vs. married women. Results of this cross-sectional study provide evidence for significant racial and demog. variations in phthalate exposure.
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    Axelson, M.; Sjövall, J.; Gustafsson, B. E.; Setchell, KDR. Origin of lignans in mammals and identification of a precursor from plants. Nature 1982, 298, 659– 660,  DOI: 10.1038/298659a0
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    Origin of lignans in mammals and identification of a precursor from plants
    Axelson, M.; Sjoevall, J.; Gustafsson, B. E.; Setchell, K. D. R.
    Nature (London, United Kingdom) (1982), 298 (5875), 659-60CODEN: NATUAS; ISSN:0028-0836.
    Evidence is presented which indicates that mammalian lignans are formed by microbial action on precursor lignans which are present as dietary constituents of plant origin. Precursors were found in seeds of different species, being particularly abundant in linseed. From this source 2,3-bis(3-methoxy-4-hydroxybenzyl)butane-1,4-diol (secoisolariciresinol) was identified as a glycoside.
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    Kang, H.; Kim, S.; Lee, G. Urinary metabolites of dibutyl phthalate and benzophenone-3 are potential chemical risk factors of chronic kidney function markers among healthy women. Environ. Int. 2019, 124, 354– 360,  DOI: 10.1016/j.envint.2019.01.028
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    Urinary metabolites of dibutyl phthalate and benzophenone-3 are potential chemical risk factors of chronic kidney function markers among healthy women
    Kang, Habyeong; Kim, Sunmi; Lee, Gowoon; Lee, Inae; Lee, Jung Pyo; Lee, Jeonghwan; Park, Hyunwoong; Moon, Hyo-Bang; Park, Jeongim; Kim, Sungkyoon; Choi, Gyuyeon; Choi, Kyungho
    Environment International (2019), 124 (), 354-360CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    Chronic kidney disease (CKD) is a global health threat of growing concern. Recently, exposure to endocrine disrupting compds. (EDCs) such as phthalates and bisphenol A has been suggested as a risk factor for CKD. However, most epidemiol. studies have focused on a limited no. of urinary chems. This study aimed to identify chem. determinants of the urinary albumin-to-creatinine ratio (ACR), which is a kidney function marker, among multiple major EDCs including phthalate metabolites, bisphenols, and benzophenones in a Korean female population (20-45 years old, n = 441). First, the creatinine-adjusted urinary concn. of each urinary chem. was assocd. with ACR in a linear regression model (single-pollutant model). Then, compds. with a significant assocn. with ACR in the single-pollutant model were added in a multi-pollutant model and evaluated for their assocn. with ACR. Moreover, to prevent potential reverse causality due to impaired kidney function, quartile analyses were performed for the subjects with healthy renal function (ACR < 9.71 mg/g). In addn. to creatinine adjustment, the statistical anal. was also conducted with sp. gr.-adjusted concns. of urinary chems., and the results were compared. Several compds. measured in the urine showed a significant assocn. with ACR in the single-pollutant model. In the multi-pollutant model, however, only monobutyl phthalate and benzophenone-1, which are metabolites of di-Bu phthalate and benzophenone-3, resp., showed significant pos. assocns. The assocn. of these chems. remained significant in a couple of the sensitivity analyses with a different adjustment of urine diln. and in a subpopulation with normal ACR. In conclusion, among dozens of urinary chems., monobutyl phthalate and benzophenone-1 consistently showed a strong assocn. with urinary ACR. Confirmation of our observation in other human populations and exptl. studies is warranted.
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    Wolff, M. S.; Teitelbaum, S. L.; McGovern, K. Environmental phenols and pubertal development in girls. Environ. Int. 2015, 84, 174– 180,  DOI: 10.1016/j.envint.2015.08.008
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    Environmental phenols and pubertal development in girls
    Wolff, Mary S.; Teitelbaum, Susan L.; McGovern, Kathleen; Pinney, Susan M.; Windham, Gayle C.; Galvez, Maida; Pajak, Ashley; Rybak, Michael; Calafat, Antonia M.; Kushi, Lawrence H.; Biro, Frank M.
    Environment International (2015), 84 (), 174-180CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
    Environmental exposures to many phenols are documented worldwide and exposures can be quite high (> 1 μM of urine metabolites). Phenols have a range of hormonal activity, but knowledge of effects on child reproductive development is limited, coming mostly from cross-sectional studies. We undertook a prospective study of pubertal development among 1239 girls recruited at three U. S. sites when they were 6-8 years old and were followed annually for 7 years to det. age at first breast or pubic hair development. Ten phenols were measured in urine collected at enrollment (benzophenone-3, enterolactone, bisphenol A, three parabens (methyl-, ethyl-, propyl-), 2,5-dichlorophenol, triclosan, genistein, daidzein). We used multivariable adjusted Cox proportional hazards ratios (HR (95% confidence intervals)) and Kaplan-Meier survival analyses to est. relative risk of earlier or later age at puberty assocd. with phenol exposures. For enterolactone and benzophenone-3, girls experienced breast development 5-6 mo later, adjusted HR 0.79 (0.64-0.98) and HR 0.80 (0.65-0.98) resp. for the 5th vs 1st quintiles of urinary biomarkers (μg/g-creatinine). Earlier breast development was seen for triclosan and 2,5-dichlorophenol: 4-9 mo sooner for 5th vs 1st quintiles of urinary concns. (HR 1.17 (0.96-1.43) and HR 1.37 (1.09-1.72), resp.). Assocn. of breast development with enterolactone, but not the other three phenols, was mediated by body size. These phenols may be antiadipogens (benzophenone-3 and enterolactone) or thyroid agonists (triclosan and 2,5-dichlorophenol), and their ubiquity and relatively high levels in children would benefit from further investigation to confirm these findings and to establish whether there are certain windows of susceptibility during which exposure can affect pubertal development.
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  1. Kalliroi Sdougkou, Stefano Papazian, Bénilde Bonnefille, Hongyu Xie, Fredrik Edfors, Linn Fagerberg, Mathias Uhlén, Göran Bergström, Leah J. Martin, Jonathan W. Martin. Longitudinal Exposomics in a Multiomic Wellness Cohort Reveals Distinctive and Dynamic Environmental Chemical Mixtures in Blood. Environmental Science & Technology 2024, 58 (37) , 16302-16315. https://doi.org/10.1021/acs.est.4c05235
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  3. Amy L. Foreman, Benedikt Warth, Ellen V. S. Hessel, Elliott J. Price, Emma L. Schymanski, Gaia Cantelli, Helen Parkinson, Helge Hecht, Jana Klánová, Jelle Vlaanderen, Klara Hilscherova, Martine Vrijheid, Paolo Vineis, Rita Araujo, Robert Barouki, Roel Vermeulen, Sophie Lanone, Søren Brunak, Sylvain Sebert, Tuomo Karjalainen. Adopting Mechanistic Molecular Biology Approaches in Exposome Research for Causal Understanding. Environmental Science & Technology 2024, 58 (17) , 7256-7269. https://doi.org/10.1021/acs.est.3c07961
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  • Abstract

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    Figure 1

    Figure 1. Dual-column setup (A) LC-HRMS system comprising two separate LC-pumps and columns combined by a T-piece before entering the mass spectrometer. (B) Gradients of both individual columns. (C) Eluent composition entering the mass spectrometer after the effluents were mixed.

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    Figure 2

    Figure 2. Comparison of the averaged peak areas of selected representative endogenous metabolites (n = 25) (A) and xenobiotics, including estrogen hormone metabolites (n = 25) (B) in solvent and urine, including a detailed overview of the averaged peak areas) relative to the highest peak area of the individual molecule from replicate injections of the samples areas (n = 4 (Comb. 4, Comb. 1); n = 6 (Comb.1, Comb. 2). The best overall combination is shaded in gray. Different columns, namely Acquity HSS T3 (HSS), SeQuant ZIC-pHILIC (ZIC), Acquity BEH Amide (BEH), and eluents, namely 0.3/0.6/1/2 mM NH4F in H2O (0.3/0.6/1/2 mM NH4F), 10 mM NH4HCO3 (pH 9.2) in H2O/ACN (9:1, v/v) (10 mM NH4HCO3), and 50 mM CH3COONH4 (pH 6) in H2O (50 mM HAc) were tested.

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    Figure 3

    Figure 3. Repeatability and accuracy in a solvent QC sample (1 μM for metabolites and xenobiotics at approximately 100 ng/mL) are reported as the number of analytes within a certain relative standard deviation of the (A) peak area and (B) retention time. The lines mark the thresholds and the labels indicate how many analytes fall below a respective RSD percentage. Only the most abundant ion species was considered for the respective column. (C) Analytes reported in SRM3672 and (D) in SRM1950 with the gray line indicating the certified reference value and the expanded uncertainty according to the certificate of analysis.

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    Figure 4

    Figure 4. Limit of detection (LOD) of representative xenobiotics and estrogens in urine (A), plasma (B), and neat solvent (C) sorted by compound classification. The values were plotted on a logarithmic scale. (D) Number of endogenous metabolites in a specific LOD range. The color indicates the category to which the analytes can be classified to.

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    Figure 5

    Figure 5. Detection of xenobiotics and endogenous estrogens in Nigerian samples. (A) Variety of observed xenobiotics including human estrogens and their classification. (B) Individual concentrations of selected analytes that have been detected in > 50% of the samples (n = 77). The human biomonitoring (HBM) guidance value for BPA (47) was added in red. (C) Extracted ion chromatograms (XICs) of selected analytes, including corresponding MS2 spectra of experimental samples and authentic reference standards. (D) Variation of analyte concentration in six individuals for selected xenobiotics demonstrates severe exposure dynamics and the need for longitudinal sampling design.

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      Background: Since 2001, researchers have examd. the human genome (G) mainly to discover causes of disease, despite evidence that G explains relatively little risk. We posit that unexplained disease risks are caused by the exposome (E; representing all exposures) and G × E interactions. Thus, etiol. research has been hampered by scientists continuing reliance on low-tech methods to characterize E compared with high-tech omics for characterizing G. Objectives: Because exposures are inherently chem. in nature and arise from both endogenous and exogenous sources, blood specimens can be used to characterize exposomes. To explore the "blood exposome" and its connection to disease, we sought human blood concns. of many chems., along with their sources, evidence of chronic-disease risks, and nos. of metabolic pathways. Methods: From the literature we obtained human blood concns. of 1,561 small mols. and metals derived from foods, drugs, pollutants, and endogenous processes. We mapped chem. similarities after weighting by blood concns., disease-risk citations, and nos. of human metabolic pathways. Results: Blood concns. spanned 11 orders of magnitude and were indistinguishable for endogenous and food chems. and drugs, whereas those of pollutants were 1,000 times lower. Chem. similarities mapped by disease risks were equally distributed by source categories, but those mapped by metabolic pathways were dominated by endogenous mols. and essential nutrients. Conclusions: For studies of disease etiol., the complexity of human exposures motivates characterization of the blood exposome, which includes all biol. active chems. Because most small mols. in blood are not human metabolites, investigations of causal pathways should expand beyond the endogenous metabolome.
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      Vermeulen, R.; Schymanski, E. L.; Barabási, A.-L.; Miller, G. W. The exposome and health: Where chemistry meets biology. Science 2020, 367, 392– 396,  DOI: 10.1126/science.aay3164
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      The exposome and health: Where chemistry meets biology
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      Science (Washington, DC, United States) (2020), 367 (6476), 392-396CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
      A review. Despite extensive evidence showing that exposure to specific chems. can lead to disease, current research approaches and regulatory policies fail to address the chem. complexity of our world. To safeguard current and future generations from the increasing no. of chems. polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chems., dietary constituents, psychosocial stressors, and phys. factors, as well as their corresponding biol. responses. Technol. advances such as high-resoln. mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
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      Exposome-Scale Investigations Guided by Global Metabolomics, Pathway Analysis, and Cognitive Computing
      Warth, Benedikt; Spangler, Scott; Fang, Mingliang; Johnson, Caroline H.; Forsberg, Erica M.; Granados, Ana; Martin, Richard L.; Domingo-Almenara, Xavier; Huan, Tao; Rinehart, Duane; Montenegro-Burke, J. Rafael; Hilmers, Brian; Aisporna, Aries; Hoang, Linh T.; Uritboonthai, Winnie; Benton, H. Paul; Richardson, Susan D.; Williams, Antony J.; Siuzdak, Gary
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      Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e., the "exposome", and their specific biol. effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technol. The authors demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biol. effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700 000 chem. structures to now include more than 950 000 unique small mols. More importantly, the authors demonstrate how the XCMS/METLIN platform now allows for the readout of the biol. effect of a toxicant through metabolomic-derived pathway anal., and further, artificial intelligence provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the methodol. challenges current exposomics research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjsV2ntr0%253D&md5=2c30f1887b1aedfde708263fe5e870a3
    7. 7
      Garratt, M.; Lagerborg, K. A.; Tsai, Y.-M.; Galecki, A.; Jain, M.; Miller, R. A. Male lifespan extension with 17-α estradiol is linked to a sex-specific metabolomic response modulated by gonadal hormones in mice. Aging Cell 2018, 17, e12786  DOI: 10.1111/acel.12786
      There is no corresponding record for this reference.
    8. 8
      Reinke, S. N.; Gallart-Ayala, H.; Gómez, C. Metabolomics analysis identifies different metabotypes of asthma severity. Eur. Respir. J. 2017, 49, 1601740  DOI: 10.1183/13993003.01740-2016
      There is no corresponding record for this reference.
    9. 9
      Ganna, A.; Salihovic, S.; Sundström, J. Large-scale Metabolomic Profiling Identifies Novel Biomarkers for Incident Coronary Heart Disease. PLoS Genet. 2014, 10, e1004801  DOI: 10.1371/journal.pgen.1004801
      9
      Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease
      Ganna, Andrea; Salihovic, Samira; Sundstroem, Johan; Broeckling, Corey D.; Hedman, Aasa K.; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Larsson, Anders; Siegbahn, Agneta; Zilmer, Mihkel; Prenni, Jessica; Aernloev, Johan; Lind, Lars; Fall, Tove; Ingelsson, Erik
      PLoS Genetics (2014), 10 (12), e1004801/1-e1004801/10, 10 pp.CODEN: PGLEB5; ISSN:1553-7404. (Public Library of Science)
      Analyses of circulating metabolites in large prospective epidemiol. studies could lead to improved prediction and better biol. understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for assocn. with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18:1 (hazard ratio [HR] per std. deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18:2 (HR = 0.81, P-value<0.001), monoglyceride 18:2 (MG 18:2; HR = 1.18, P-value = 0.011) and sphingomyelin 28:1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addn. to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18:2 was assocd. with CHD independently of triglycerides. Lysophosphatidylcholines were neg. assocd. with body mass index, C-reactive protein and with less evidence of subclin. cardiovascular disease in addnl. 970 participants; a reverse pattern was obsd. for MG 18:2. MG 18:2 showed an enrichment (P-value = 0.002) of significant assocns. with CHD-assocd. SNPs (P-value = 1.2 × 10-7 for assocn. with rs964184 in the ZNF259/APOA5 region) and a weak, but pos. causal effect (odds ratio = 1.05 per SD increment in MG 18:2, P-value = 0.05) on CHD, as suggested by Mendelian randomization anal. In conclusion, we identified four lipid-related metabolites with evidence for clin. utility, as well as a causal role in CHD development.
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    10. 10
      Rhoades, S. D.; Sengupta, A.; Weljie, A. M. Time is ripe: maturation of metabolomics in chronobiology. Curr. Opin. Biotechnol. 2017, 43, 70– 76,  DOI: 10.1016/j.copbio.2016.09.007
      10
      Time is ripe: maturation of metabolomics in chronobiology
      Rhoades, Seth D.; Sengupta, Arjun; Weljie, Aalim M.
      Current Opinion in Biotechnology (2017), 43 (), 70-76CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
      A review. Sleep and circadian rhythms studies have recently benefited from metabolomics analyses, uncovering new connections between chronobiol. and metab. From untargeted mass spectrometry to quant. NMR spectroscopy, a diversity of anal. approaches has been applied for biomarker discovery in the field. In this review we consider advances in the application of metabolomics technologies which have uncovered significant effects of sleep and circadian cycles on several metabolites, namely phosphatidylcholine species, medium-chain carnitines, and arom. amino acids. Study design and data processing measures essential for detecting rhythmicity in metabolomics data are also discussed. Future developments in these technologies are anticipated vis-a-vis validating early findings, given metabolomics has only recently entered the ring with other systems biol. assessments in chronometabolism studies.
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    11. 11
      Hu, X.; Walker, D. I.; Liang, Y. A scalable workflow to characterize the human exposome. Nat. Commun. 2021, 12, 5575  DOI: 10.1038/s41467-021-25840-9
      11
      A scalable workflow to characterize the human exposome
      Hu, Xin; Walker, Douglas I.; Liang, Yongliang; Smith, Matthew Ryan; Orr, Michael L.; Juran, Brian D.; Ma, Chunyu; Uppal, Karan; Koval, Michael; Martin, Greg S.; Neujahr, David C.; Marsit, Carmen J.; Go, Young-Mi; Pennell, Kurt D.; Miller, Gary W.; Lazaridis, Konstantinos N.; Jones, Dean P.
      Nature Communications (2021), 12 (1), 5575CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      Abstr.: Complementing the genome with an understanding of the human exposome is an important challenge for contemporary science and technol. Tens of thousands of chems. are used in commerce, yet cost for targeted environmental chem. anal. limits surveillance to a few hundred known hazards. To overcome limitations which prevent scaling to thousands of chems., we develop a single-step express liq. extn. and gas chromatog. high-resoln. mass spectrometry anal. to operationalize the human exposome. We show that the workflow supports quantification of environmental chems. in human plasma (200 μL) and tissue (≤100 mg) samples. The method also provides high resoln., sensitivity and selectivity for exposome epidemiol. of mass spectral features without a priori knowledge of chem. identity. The simplicity of the method can facilitate harmonization of environmental biomonitoring between labs. and enable population level human exposome research with limited sample vol.
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    12. 12
      Jacob, M.; Lopata, A. L.; Dasouki, M.; Rahman, A. M. A. Metabolomics toward personalized medicine. Mass Spectrom. Rev. 2019, 38, 221– 238,  DOI: 10.1002/mas.21548
      12
      Metabolomics toward personalized medicine
      Jacob, Minnie; Lopata, Andreas L.; Dasouki, Majed; Abdel Rahman, Anas M.
      Mass Spectrometry Reviews (2019), 38 (3), 221-238CODEN: MSRVD3; ISSN:0277-7037. (John Wiley & Sons, Inc.)
      A review. Metabolomics, which is the metabolites profiling in biol. matrixes, is a key tool for biomarker discovery and personalized medicine and has great potential to elucidate the ultimate product of the genomic processes. Over the last decade, metabolomics studies have identified several relevant biomarkers involved in complex clin. phenotypes using diverse biol. systems. Most diseases result in signature metabolic profiles that reflect the sums of external and internal cellular activities. Metabolomics has a major role in clin. practice as it represents >95% of the workload in clin. labs. worldwide. Many of these metabolites require different anal. platforms, such as NMR (NMR), Mass Spectrometry (MS), and Ultra Performance Liq. Chromatog. (UPLC), while many clin. relevant metabolites are still not routinely amenable to detection using currently available assays. Combining metabolomics with genomics, transcriptomics, and proteomics studies will result in a significantly improved understanding of the disease mechanisms and the pathophysiol. of the target clin. phenotype. This comprehensive approach will represent a major step forward toward providing precision medical care, in which individual is accounted for variability in genes, environment, and personal lifestyle. In this review, we compare and evaluate the metabolomics strategies and studies that focus on the discovery of biomarkers that have "personalized" diagnostic, prognostic, and therapeutic value, validated for monitoring disease progression and responses to various management regimens.
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    13. 13
      Prasain, J. K.; Arabshahi, A.; Moore, D. R., 2nd; Greendale, G. A.; Wyss, J. M.; Barnes, S. Simultaneous determination of 11 phytoestrogens in human serum using a 2 min liquid chromatography/tandem mass spectrometry method. J. Chromatogr. B 2010, 878, 994– 1002,  DOI: 10.1016/j.jchromb.2010.02.032
      13
      Simultaneous determination of 11 phytoestrogens in human serum using a 2 min liquid chromatography/tandem mass spectrometry method
      Prasain, Jeevan K.; Arabshahi, Alireza; Moore, D. Ray; Greendale, Gail A.; Wyss, J. Michael; Barnes, Stephen
      Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2010), 878 (13-14), 994-1002CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
      A rapid 2 min liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method operating in multiple reaction ion monitoring mode was developed and validated that allows for the characterization and simultaneous quantification of 11 phytoestrogen metabolites with mass transitions m/z 241/119 (equol), 253/132 (daidzein), 255/149 (dihydrodaidzein), 257/108 (O-desmethylangolesin), 269/133 (genistein), 283/184 (glycitein), 267/191 (formononetin), 289/109 (biochanin A), 267/91 (coumestrol), enterodiol (301/253), and enterolactone (297/253). The method was demonstrated to be specific and sensitive, and a linear response for each phytoestrogen was obsd. over a range of 1-5000 ng/mL in human serum with the exception of dihydrodaidzein, whose lower limit of quantification was 2 ng/mL. The sepn. was carried out on a Synergi Polar-RP 2.5 μ (50 mm × 2.0 mm i.d.) column at 50 °C with water and acetonitrile (both contg. 10 mM ammonium acetate) as the mobile phase under gradient conditions at a flow rate of 0.75 mL/min. This LC-MS/MS method is very useful for high-throughput anal. of phytoestrogens and proved to be simple, sensitive, reproducible, and reliable.
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    14. 14
      Vela-Soria, F.; Jiménez-Díaz, I.; Rodríguez-Gómez, R. Determination of benzophenones in human placental tissue samples by liquid chromatography–tandem mass spectrometry. Talanta 2011, 85, 1848– 1855,  DOI: 10.1016/j.talanta.2011.07.030
      14
      Determination of benzophenones in human placental tissue samples by liquid chromatography-tandem mass spectrometry
      Vela-Soria, F.; Jimenez-Diaz, I.; Rodriguez-Gomez, R.; Zafra-Gomez, A.; Ballesteros, O.; Navalon, A.; Vilchez, J. L.; Fernandez, M. F.; Olea, N.
      Talanta (2011), 85 (4), 1848-1855CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
      Benzophenones (BPs) are a family of compds. widely used to protect the skin and hair from UV irradn. Despite human exposure to BPs through dermal application of products contg. sunscreen agents and the increasing evidence that BPs are able to interfere with endocrine systems, few studies have examd. the occurrence of BPs in humans. In this work, the authors propose a new liq. chromatog.-tandem mass spectrometry (LC-MS/MS) method to det. 6 BPs, namely, benzophenone-1 (BP-1), benzophenone-2 (BP-2), benzophenone-3 (BP-3), benzophenone-6 (BP-6), benzophenone-8 (BP-8) and 4-hydroxybenzophenone (4-OH-BP) in human placental tissue samples. The method involves an extn. step of the analytes from the samples using Et acetate, followed by a clean-up step using centrifugation prior to their quantification by LC-MS/MS using an atm. pressure chem. ionization (APCI) interface in the pos. mode. Benzophenone-d10 (BP-d10) was used as surrogate. Found detection limits (LOD) ranged from 0.07 to 0.3 ng g-1 and quantification limits (LOQ) from 0.3 to 1.0 ng g-1, while inter- and intra-day variability was under 5%. The method was validated using std. addn. calibration and a recovery assay. Recovery rates for spiked samples ranged from 98 to 104%. This method was satisfactorily applied for the detn. of BPs in 16 placental tissue samples collected from women who live in Granada (Spain).
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    15. 15
      Azzouz, A.; Rascón, A. J.; Ballesteros, E. Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography–mass spectrometry. J. Pharm. Biomed. Anal. 2016, 119, 16– 26,  DOI: 10.1016/j.jpba.2015.11.024
      15
      Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography-mass spectrometry
      Azzouz, Abdelmonaim; Rascon, Andres J.; Ballesteros, Evaristo
      Journal of Pharmaceutical and Biomedical Analysis (2016), 119 (), 16-26CODEN: JPBADA; ISSN:0731-7085. (Elsevier B.V.)
      A highly sensitive gas chromatog.-mass spectrometry (GC-MS) method for the detn. of endocrine disrupting chems. (EDCs) including parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human breast milk, blood and urine samples is proposed. Blood and milk require a pretreatment to remove proteins and other substances potentially interfering with the continuous solid-phase extn. (SPE) system used; urine samples can be directly introduced into the system after filtering. Analytes are retained on a LiChrolut EN column and derivatized by silylation following elution with acetonitrile. The resulting trimethylsilyl derivs. are detd. by GC-MS. The proposed method exhibited good linearity (R2 >0.995) for all target EDCs over the concn. range 0.7-10,000 ng/l in urine, and 3.3-50,000 ng/l in blood and milk. Also, it provided low limits of detection (0.2-1.8 ng/l in urine, and 1.0-9.0 ng/l in blood and milk), good precision (relative std. deviations less than 7%) and recoveries from 86 to 104%. A total of 24 human fluid samples were analyzed and most found to contain some target EDC at concns. from 0.10 to 14 μg/l.
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    16. 16
      de Oliveira, M. L.; Rocha, B. A.; Souza, VCdO.; Barbosa, F. Determination of 17 potential endocrine-disrupting chemicals in human saliva by dispersive liquid-liquid microextraction and liquid chromatography-tandem mass spectrometry. Talanta 2019, 196, 271– 276,  DOI: 10.1016/j.talanta.2018.12.067
      16
      Determination of 17 potential endocrine-disrupting chemicals in human saliva by dispersive liquid-liquid microextraction and liquid chromatography-tandem mass spectrometry
      de Oliveira Mariana Lepri; Rocha Bruno Alves; Souza Vanessa Cristina de Oliveira; Barbosa Fernando Jr
      Talanta (2019), 196 (), 271-276 ISSN:.
      Endocrine-disrupting chemicals are a group of emerging contaminants that alters the function of the endocrine system, causing possible adverse health effects. In this study, a dispersive liquid-liquid microextraction method coupled with liquid chromatography-mass spectrometry for the simultaneous determination of 17 potential EDCs, bisphenols (A, S, P, AP, AF, Z), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben), benzophenones (3, 1, 2, 8, 4-OH BP) and triclocarban, in human saliva samples was developed. Several parameters such as, type and volume of extraction and dispersive solvents, pH sample, ionic strength and, agitation, that affect extraction efficiency were investigated. Under the optimized conditions, the matrix-matched calibration curves of all analytes presented correlation coefficients higher than 0.99 (range level of 1-20 ng mL(-1)). The intra and inter-day coefficient of variation and relative standard deviation were lower than 20%, at 1 ng mL(-1). The limits of detection and quantification ranged from 0.01 to 0.15 ng mL(-1) and 0.05-0.40 ng mL(-1), respectively. Finally, the proposed method was applied in the simultaneous determination of several endocrine-disrupting chemicals classes in 10 human saliva samples In conclusion, the proposed method is an attractive alternative for application in large-scale human biomonitoring studies.
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    17. 17
      Kolatorova Sosvorova, L.; Chlupacova, T.; Vitku, J. Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS. Talanta 2017, 174, 21– 28,  DOI: 10.1016/j.talanta.2017.05.070
      17
      Determination of selected bisphenols, parabens and estrogens in human plasma using LC-MS/MS
      Kolatorova Sosvorova, Lucie; Chlupacova, Tereza; Vitku, Jana; Vlk, Martin; Heracek, Jiri; Starka, Luboslav; Saman, David; Simkova, Marketa; Hampl, Richard
      Talanta (2017), 174 (), 21-28CODEN: TLNTA2; ISSN:0039-9140. (Elsevier B.V.)
      In this study, a novel liq. chromatog. - tandem mass spectrometry method for the simultaneous detn. of bisphenols (BPA, BPS, BPF, BPAF), parabens (methyl-, ethyl-, propyl-, butyl-, benzyl-paraben) and estrogens (estrone, estradiol, estriol) in human plasma is presented. Since all analytes possess the phenolic group, dansyl chloride derivatization was applied in order to gain high sensitivity. The method was validated according to FDA guidelines, and all validation requirements were satisfactory. The lower limits of quantifications were 41.6, 54.9, 43.5 and 150.8 pg/mL for BPA, BPS, BPF and BPAF; 172, 149, 171, 134 and 202 pg/mL for methyl-, ethyl-, propyl-, butyl- and benzyl-paraben; 10.5, 6.7 and 9.4 pg/mL for estrone, estradiol and estriol, resp. This is the first method allowing the detn. of plasma bisphenols, parabens and estrogens in one run, and also the first detn. of BPF levels in human plasma. The method was used to examine the plasma levels of healthy normospermic men, where three times higher plasma levels of BPF than BPA were found.
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    18. 18
      Braun, D.; Ezekiel, C. N.; Abia, W. A. Monitoring Early Life Mycotoxin Exposures via LC-MS/MS Breast Milk Analysis. Anal. Chem. 2018, 90, 14569– 14577,  DOI: 10.1021/acs.analchem.8b04576
      18
      Monitoring Early Life Mycotoxin Exposures via LC-MS/MS Breast Milk Analysis
      Braun, Dominik; Ezekiel, Chibundu N.; Abia, Wilfred A.; Wisgrill, Lukas; Degen, Gisela H.; Turner, Paul C.; Marko, Doris; Warth, Benedikt
      Analytical Chemistry (Washington, DC, United States) (2018), 90 (24), 14569-14577CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      Infants are particularly susceptible toward the toxic effects of food contaminants, including mycotoxins. However, multimycotoxin exposure assessment in breast milk has received very limited attention so far, resulting in a poor understanding of coexposures during early life. Here, we present the development and application of a highly sensitive, specific, and quant. assay assessing up to 28 mycotoxins, including regulated (aflatoxins, ochratoxin A, deoxynivalenol, zearalenone) and emerging mycotoxins as well as key metabolites by LC-MS/MS. After careful optimization of the sample prepn. procedure, a QuEChERS protocol combined with a freeze-out step was validated inhouse. The limits of quantification varied between 0.009 and 2.9 ng/mL, and for most analytes extn. recovery (74-116%) and intermediate precision (2-20%) were satisfactory. The method was applied to examine multiple breast milk samples obtained from 22 women (n = 75 in total) from Ogun State, Nigeria. Most samples were either entirely free of mycotoxins or contaminated to a minimal extent with beauvericin (56%), enniatin B (9%), ochratoxin A (15%), and aflatoxin M1 (1%). The most abundant mycotoxin was beauvericin, which was not reported in this biol. fluid before, with concns. up to 0.019 ng/mL. In conclusion, the method demonstrated to be fit for purpose to det. and quantify low background contaminations in human breast milk. On the basis of the high sensitivity of the novel anal. method, it was possible to deduce that tolerable daily intake values were not exceeded by breastfeeding in the examd. infants.
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    19. 19
      Šarkanj, B.; Ezekiel, C. N.; Turner, P. C. Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers. Anal. Chim. Acta 2018, 1019, 84– 92,  DOI: 10.1016/j.aca.2018.02.036
      19
      Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers
      Sarkanj, Bojan; Ezekiel, Chibundu N.; Turner, Paul C.; Abia, Wilfred A.; Rychlik, Michael; Krska, Rudolf; Sulyok, Michael; Warth, Benedikt
      Analytica Chimica Acta (2018), 1019 (), 84-92CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
      There is a crit. need to better understand the patterns, levels and combinatory effects of exposures the authors are facing through the authors' diet and environment. Mycotoxin mixts. are of particular concern due to chronic low dose exposures caused by naturally contaminated food. To facilitate new insights into their role in chronic disease, mycotoxins and their metabolites are quantified in bio-fluids as biomarkers of exposure. Here, the authors describe a highly sensitive urinary assay based on ultra-HPLC - tandem mass spectrometer (UHPLC-MS/MS) and 13C-labeled or deuterated internal stds. covering the most relevant regulated and emerging mycotoxins. Utilizing enzymic pre-treatment, solid phase extn. and UHPLC sepn., the sensitivity of the method was significantly higher (10-160x lower LODs) than in a previously described method used for comparison purpose, and stable isotopes provided compensation for challenging matrix effects. This method was inhouse validated and applied to re-assess mycotoxin exposure in urine samples obtained from Nigerian children, adolescent and adults, naturally exposed through their regular diet. Owing to the methods high sensitivity, biomarkers were detected in all samples. The mycoestrogen zearalenone was the most frequently detected contaminant (82%) but also ochratoxin A (76%), aflatoxin M1 (73%) and fumonisin B1 (71%) were quantified in a large share of urines. Overall, 57% of 120 urines were contaminated with both, aflatoxin M1 and fumonisin B1, and other co-exposures were frequent. These results clearly demonstrate the advanced performance of the method to assess lowest background exposures (pg mL-1 range) using a single, highly robust assay that will allow for the systematic investigation of low dose effects on human health.
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    20. 20
      Jamnik, T.; Flasch, M.; Braun, D. Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development. Nat. Commun. 2022, 13, 2653
      20
      Next-generation biomonitoring of the early-life chemical exposome in neonatal and infant development
      Jamnik, Thomas; Flasch, Mira; Braun, Dominik; Fareed, Yasmin; Wasinger, Daniel; Seki, David; Berry, David; Berger, Angelika; Wisgrill, Lukas; Warth, Benedikt
      Nature Communications (2022), 13 (1), 2653CODEN: NCAOBW; ISSN:2041-1723. (Nature Portfolio)
      Exposure to synthetic and natural chems. is a major environmental risk factor in the etiol. of many chronic diseases. Investigating complex co-exposures is necessary for a holistic assessment in exposome-wide assocn. studies. In this work, a sensitive liq. chromatog.-tandem mass spectrometry approach was developed and validated. The assay enables the anal. of more than 80 highly-diverse xenobiotics in urine, serum/plasma, and breast milk; with detection limits generally in the pg-ng mL-1 range. In plasma of extremely-premature infants, 27 xenobiotics are identified; including contamination with plasticizers, perfluorinated alkylated substances and parabens. In breast milk samples collected longitudinally over the first 211 days post-partum, 29 analytes are detected, including pyrrolizidine- and tropane alkaloids which have not been identified in this matrix before. A preliminary estn. of daily toxicant intake via breast milk is conducted. In conclusion, we observe significant early-life co-exposure to multiple toxicants, and demonstrate the method's applicability for large-scale exposomics-type cohort studies.
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    21. 21
      Marin, S.; Ramos, A. J.; Cano-Sancho, G.; Sanchis, V. Mycotoxins: Occurrence, toxicology, and exposure assessment. Food Chem. Toxicol. 2013, 60, 218– 237,  DOI: 10.1016/j.fct.2013.07.047
      21
      Mycotoxins: Occurrence, toxicology, and exposure assessment
      Marin, S.; Ramos, A. J.; Cano-Sancho, G.; Sanchis, V.
      Food and Chemical Toxicology (2013), 60 (), 218-237CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)
      A review. Mycotoxins are abiotic hazards produced by certain fungi that can grow on a variety of crops. Consequently, their prevalence in plant raw materials may be relatively high. The concn. of mycotoxins in finished products is usually lower than in raw materials. In this review, occurrence and toxicol. of the main mycotoxins are summarised. Furthermore, methodol. approaches for exposure assessment are described. Existing exposure assessments, both through contamination and consumption data and biomarkers of exposure, for the main mycotoxins are also discussed.
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    22. 22
      Xu, Z.; Liu, J.; Wu, X.; Huang, B.; Pan, X. Nonmonotonic responses to low doses of xenoestrogens: A review. Environ. Res. 2017, 155, 199– 207,  DOI: 10.1016/j.envres.2017.02.018
      22
      Nonmonotonic responses to low doses of xenoestrogens: A review
      Xu, Zhixiang; Liu, Jun; Wu, Xinhao; Huang, Bin; Pan, Xuejun
      Environmental Research (2017), 155 (), 199-207CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
      A review. Xenoestrogens (XEs) mimic or block the synthesis, metab. and transport of normal endogenous hormones, disturbing normal endocrine function. The available data on the nonmonotonic estrogenic effects of low doses of many XEs are reviewed, covering in vitro, in vivo and epidemiol. studies. The obsd. nonmonotonic patterns of the dose-response curves are discussed, along with possible underlying mechanisms. This review is intended to provide guidance for harm predication and to suggest prevention measures.
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    23. 23
      Christiansen, S.; Marta, A.; Julie, B.; Anne Marie, V.; Gitte Alsing, P.; Ulla, H. Low-dose effects of bisphenol A on early sexual development in male and female rats. Reproduction 2014, 147, 477– 487,  DOI: 10.1530/REP-13-0377
      23
      Low-dose effects of bisphenol a on early sexual development in male and female rats
      Christiansen, Sofie; Axelstad, Marta; Boberg, Julie; Vinggaard, Anne Marie; Pedersen, Gitte Alsing; Hass, Ulla
      Reproduction (Bristol, United Kingdom) (2014), 147 (4), 477-487CODEN: RCUKBS; ISSN:1470-1626. (Bioscientifica Ltd.)
      Bisphenol A (BPA) is widely detected in human urine and blood. BPA has been reported to impair many endpoints for reproductive and neurol. development; however, it is controversial whether BPA has effects in the microgram per kg dose range. The aim of the current study was to examine the influence of BPA on early sexual development in male and female rats at dose levels covering both regulatory no obsd. adverse effect levels (NOAELs) (5 and 50 mg/kg bw per day) as well as doses in the microgram per kg dose range (0.025 and 0.25 mg/kg bw per day). Time-mated Wistar rats (n = 22) were gavaged during pregnancy and lactation from gestation day 7 to pup day 22 with 0, 0.025, 0.25, 5 or 50 mg/kg bw per day BPA. From 0.250 mg/kg and above, male anogenital distance (AGD) was significantly decreased, whereas decreased female AGD was seen from 0.025 mg/kg bw per day and above. Moreover, the incidence of nipple retention in males appeared to increase dose relatedly and the increase was statistically significant at 50 mg/kg per day. No significant changes in reproductive organ wts. in the 16-day-old males and females and no signs of maternal toxicity were seen. The decreased AGD at birth in both sexes indicates effects on prenatal sexual development and provides new evidence of low-dose adverse effects of BPA in rats in the microgram per kg dose range. The NOAEL in this study is clearly below 5 mg/kg for BPA, which is used as the basis for establishment of the current tolerable daily intake (TDI) by EFSA; thus a reconsideration of the current TDI of BPA appears warranted.
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    24. 24
      Paterni, I.; Granchi, C.; Minutolo, F. Risks and benefits related to alimentary exposure to xenoestrogens. Crit. Rev. Food Sci. Nutr. 2017, 57, 3384– 3404,  DOI: 10.1080/10408398.2015.1126547
      24
      Risks and benefits related to alimentary exposure to xenoestrogens
      Paterni, Ilaria; Granchi, Carlotta; Minutolo, Filippo
      Critical Reviews in Food Science and Nutrition (2017), 57 (16), 3384-3404CODEN: CRFND6; ISSN:1040-8398. (Taylor & Francis, Inc.)
      Xenoestrogens are widely diffused in the environment and in food, thus a large portion of human population worldwide is exposed to them. Among alimentary xenoestrogens, phytoestrogens (PhyEs) are increasingly being consumed because of their potential health benefits, although there are also important risks assocd. to their ingestion. Furthermore, other xenoestrogens that may be present in food are represented by other chems. possessing estrogenic activities, that are commonly defined as endocrine disrupting chems. (EDCs). EDCs pose a serious health concern since they may cause a wide range of health problems, starting from pre-birth till adult lifelong exposure. We herein provide an overview of the main classes of xenoestrogens, which are classified on the basis of their origin, their structures and their occurrence in the food chain. Furthermore, their either beneficial or toxic effects on human health are discussed in this review.
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    25. 25
      Chung, M. K.; Buck Louis, G. M.; Kannan, K.; Patel, C. J. Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes. Environ. Int. 2019, 125, 505– 514,  DOI: 10.1016/j.envint.2018.11.037
      25
      Exposome-wide association study of semen quality: Systematic discovery of endocrine disrupting chemical biomarkers in fertility require large sample sizes
      Chung, Ming Kei; Buck Louis, Germaine M.; Kannan, Kurunthachalam; Patel, Chirag J.
      Environment International (2019), 125 (), 505-514CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      Exposome-wide assocn. studies (EWAS) are a systematic and unbiased way to investigate multiple environmental factors assocd. with phenotype. We applied EWAS to study semen quality and queried the sample size requirements to detect modest assocns. in a reproductive cohort. We conducted 1. a multivariate EWAS of 128 endocrine disrupting chems. (EDCs) from 15 chem. classes measured in urine/serum relative to 7 semen quality endpoints in a prospective cohort study comprising 473 men and 2. estd. the sample size requirements for EWAS etiol. investigations. None of the EDCs were assocd. with semen quality endpoints after adjusting for multiple tests. However, several EDCs (e.g., polychlorinated biphenyl congeners 99, 105, 114, and 167) were assocd. with raw p < 0.05. In a post hoc statistical power anal. with the obsd. effect sizes, we detd. that EWAS research in male fertility will require a mean sample size of 2696 men (1795-3625) to attain a power of 0.8. The av. size of four published studies is 201 men. Existing cohort studies with hundreds of participants are underpowered (<0.8) for EWAS-related investigations. Merging cohorts to ensure a sufficient sample size can facilitate the use of EWAS methods for assessing EDC mixts. that impact semen quality.
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    26. 26
      Rampler, E.; Abiead, Y. E.; Schoeny, H. Recurrent Topics in Mass Spectrometry-Based Metabolomics and Lipidomics─Standardization, Coverage, and Throughput. Anal. Chem. 2021, 93, 519– 545,  DOI: 10.1021/acs.analchem.0c04698
      26
      Recurrent Topics in Mass Spectrometry-Based Metabolomics and Lipidomics-Standardization, Coverage, and Throughput
      Rampler, Evelyn; El Abiead, Yasin; Schoeny, Harald; Rusz, Mate; Hildebrand, Felina; Fitz, Veronika; Koellensperger, Gunda
      Analytical Chemistry (Washington, DC, United States) (2021), 93 (1), 519-545CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
      There is no expanded citation for this reference.
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    27. 27
      Liu, X.; Zhou, L.; Shi, X.; Xu, G. New advances in analytical methods for mass spectrometry-based large-scale metabolomics study. TrAC, Trends Anal. Chem. 2019, 121, 115665  DOI: 10.1016/j.trac.2019.115665
      27
      New advances in analytical methods for mass spectrometry-based large-scale metabolomics study
      Liu, Xinyu; Zhou, Lina; Shi, Xianzhe; Xu, Guowang
      TrAC, Trends in Analytical Chemistry (2019), 121 (), 115665CODEN: TTAEDJ; ISSN:0165-9936. (Elsevier B.V.)
      A Review. Large-scale metabolomics study based on large population cohorts is increasingly applied to identify important metabolites or crit. metabolic alterations related to the metabolite perturbation in disease states or under interventions and to investigate metabolic difference and stimuli response in genetically different individuals. Mass spectrometry (MS) coupled with different chromatog. methods, is suitable for large-scale metabolomics study due to its high sensitivity and selectivity, wide dynamic range, and rich information. However, there are still a series of challenges for really realizing large-scale metabolomics applications. Hence, in this review, we mainly focused on new advances in sample pretreatment methods, nontargeted, targeted and pseudotargeted metabolic data collection techniques, and data correction methods used for MS-based large-scale metabolomics study. Typical applications of MS-based large-scale metabolomics methods in mol. epidemiol., precision medicine, and genome-wide assocn. studies with metabolomics (mGWAS) are also given.
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    28. 28
      Schwaiger, M.; Schoeny, H.; El Abiead, Y.; Hermann, G.; Rampler, E.; Koellensperger, G. Merging metabolomics and lipidomics into one analytical run. Analyst 2019, 144, 220– 229,  DOI: 10.1039/C8AN01219A
      28
      Merging metabolomics and lipidomics into one analytical run
      Schwaiger, Michaela; Schoeny, Harald; El Abiead, Yasin; Hermann, Gerrit; Rampler, Evelyn; Koellensperger, Gunda
      Analyst (Cambridge, United Kingdom) (2019), 144 (1), 220-229CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)
      A novel integrated metabolomics/lipidomics workflow is introduced enabling high coverage of polar metabolites and non-polar lipids within one anal. run. Dual HILIC and RP chromatog. were combined to high-resoln. mass spectrometry. As a major advantage, only one data file per sample was obtained by fully automated simultaneous anal. of two exts. per sample. Hence, the unprecedented high coverage without compromise on anal. throughput was not only obtained by the orthogonality of the chromatog. sepns., but also by the implementation of dedicated sample prepn. procedures resulting in optimum extn. efficiency for both sub-omes. Thus, the method addressed completely hydrophilic sugars and org. acids next to water-insol. triglycerides. As for the timing of the dual chromatog. setup, HILIC and RP sepn. were performed consecutively. However, re-equilibration of the HILIC column during elution of RP compds. and vice versa reduced the overall anal. time by one third to 32 min. Application to the Std. Ref. Material SRM 1950 - Metabolites in Frozen Human Plasma resulted in >100 metabolite and >380 lipid identifications based on accurate mass implementing fast polarity switching and acquiring data dependent MS2 spectra with the use of automated exclusion lists. Targeted quantification based on external calibrations and 13C labeled yeast internal stds. was successfully accomplished for 59 metabolites. Moreover, the potential for lipid quantification was shown integrating non-endogenous lipids as internal stds. In human plasma, concns. ranging over 4 orders of magnitude (low nM to high μM) were assessed.
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    29. 29
      Fitz, V.; El Abiead, Y.; Berger, D.; Koellensperger, G. Systematic Investigation of LC Miniaturization to Increase Sensitivity in Wide-Target LC-MS-Based Trace Bioanalysis of Small Molecules. Front. Mol. Biosci. 2022, 9, 857505  DOI: 10.3389/fmolb.2022.857505
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      Systematic investigation of LC miniaturization to increase sensitivity in wide-target LC-MS-based trace bioanalysis of small molecules
      Fitz, Veronika; El Abiead, Yasin; Berger, Daniel; Koellensperger, Gunda
      Frontiers in Molecular Biosciences (2022), 9 (), 857505CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)
      Covering a wide spectrum of mols. is essential for global metabolome assessment. While metabolomics assays are most frequently carried out in microbore LC-MS anal., reducing the size of the anal. platform has proven its ability to boost sensitivity for specific -omics applications. In this study, we elaborate the impact of LC miniaturization on exploratory smallmol. LC-MS anal., focusing on chromatog. properties with crit. impact on peak picking and statistical anal. We have assessed a panel of small mols. comprising endogenous metabolites and environmental contaminants covering three flow regimes-anal., micro-, and nano-flow. Miniaturization to the micro-flow regime yields moderately increased sensitivity as compared to the nano setup, where median sensitivity gains around 80-fold are obsd. in protein-pptd. blood plasma ext. This gain resulting in higher coverage at low μg/L concns. is compd. dependent. At the same time, the nano-LC-high-resoln. mass spectrometry (HRMS) approach reduces the investigated chem. space as a consequence of the trap-and-elute nano-LC platform. Finally, while all three setups show excellent retention time stabilities, rapid gradients jeopardize the peak area repeatability of the nano-LC setup. Micro-LC offers the best compromise between improving signal intensity and metabolome coverage, despite the fact that only incremental gains can be achieved. Hence, we recommend using micro-LC for wide-target small-mol. trace bioanal. and global metabolomics of abundant samples.
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    30. 30
      Bloszies, C. S.; Fiehn, O. Using untargeted metabolomics for detecting exposome compounds. Curr. Opin. Toxicol. 2018, 8, 87– 92,  DOI: 10.1016/j.cotox.2018.03.002
      There is no corresponding record for this reference.
    31. 31
      Oesterle, I.; Braun, D.; Rompel, A.; Warth, B. Quantifying up to 90 polyphenols simultaneously in human bio-fluids by LC-MS/MS. Anal. Chim. Acta 2022, 1216, 339977,  DOI: 10.1016/j.aca.2022.339977
      55
      Quantifying up to 90 polyphenols simultaneously in human bio-fluids by LC-MS/MS
      Oesterle, Ian; Braun, Dominik; Rompel, Annette; Warth, Benedikt
      Analytica Chimica Acta (2022), 1216 (), 339977CODEN: ACACAM; ISSN:0003-2670. (Elsevier B.V.)
      Establishing a method for human biomonitoring (HBM) of polyphenols enables the assessment of internal concns. of these food bio-actives and the correlation with potential health effects such as antioxidant or anti-inflammatory properties. Thus, a targeted LC-MS/MS method for quantifying up to 90 analytes, representing the main polyphenol classes including flavanones, isoflavones, stilbenes, and phenolic acids, was developed for human urine, serum, and plasma. The method was established for low sample vols. and with a cost and time efficient sample prepn. protocol for high-throughput, which is crit. for its application in large cohort and exposome-wide assocn. studies. On av., the sample prepn. yielded extn. efficiencies of 98% for urine, 98% for serum, and 87% for plasma. Limits of detection were between 0.11 ng mL-1 and 300 ng mL-1 for urine, 0.12 ng mL-1 and 190 ng mL-1 for serum, and 0.12 ng mL-1 and 340 ng mL-1 for plasma, excluding one analyte. Inhouse validation revealed that 66, 49, and 64 analytes for urine, serum, and plasma, resp., fulfilled all stringent requirements, that are usually utilized for tailored single analyte methods, at all evaluated concn. levels. After validation, this method was applied in a proof-of-principle study that detected 39 polyphenols in urine. Changes in the concns. of the analytes after the ingestion of a high polyphenol smoothie was examd. over 24 h. The study further confirmed that the majority of polyphenols detected were phenolic acids, and phase II conjugated metabolites were more abundant than their resp. non-conjugated forms.
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    32. 32
      Braun, D.; Abia, W. A.; Šarkanj, B. Mycotoxin-mixture assessment in mother-infant pairs in Nigeria: From mothers’ meal to infants’ urine. Chemosphere 2022, 287, 132226  DOI: 10.1016/j.chemosphere.2021.132226
      31
      Mycotoxin-mixture assessment in mother-infant pairs in Nigeria: From mothers' meal to infants'urine
      Braun, Dominik; Abia, Wilfred A.; Sarkanj, Bojan; Sulyok, Michael; Waldhoer, Thomas; Erber, Astrid C.; Krska, Rudolf; Turner, Paul C.; Marko, Doris; Ezekiel, Chibundu N.; Warth, Benedikt
      Chemosphere (2022), 287 (Part_2), 132226CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
      Exposure to food and environmental contaminants is a global environmental health issue. In this study, innovative LC-MS/MS approaches were applied to investigate mycotoxin co-exposure in mother-infant pairs (n = 23) by analyzing matched plate-ready food, breast milk and urine samples of mothers and their exclusively breastfed infants. The study revealed frequent co-occurrence of two to five mycotoxins. Regulated (e.g. aflatoxins, deoxynivalenol and ochratoxin A) and emerging mycotoxins (e.g. alternariol monomethyl ether and beauvericin) were frequently detected (3%-89% and 45%-100%), in at least one specimen. In addn., a moderate assocn. of ochratoxin A in milk to urine of mothers (r = 0.47; p = 0.003) and infants (r = 0.52; p = 0.019) but no other significant correlations were found. Av. concn. levels in food mostly did not exceed European max. residue limits, and intake ests. demonstrated exposure below tolerable daily intake values. Infants were exposed to significantly lower toxin levels compared to their mothers, indicating the protective effect of breastfeeding. However, the transfer into milk and urine and the resulting chronic low-dose exposure warrant further monitoring. In the future, occurrence of mycotoxin-mixts., and their combined toxicol. effects need to be comprehensively considered and implemented in risk management strategies. These should aim to minimize early-life exposure in crit. developmental stages.
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    33. 33
      Narduzzi, L.; Royer, A.-L.; Bichon, E. Ammonium Fluoride as Suitable Additive for HILIC-Based LC-HRMS Metabolomics. Metabolites 2019, 9, 292  DOI: 10.3390/metabo9120292
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      Ammonium fluoride as suitable additive for HILIC-based LC-HRMS metabolomics
      Narduzzi, Luca; Royer, Anne-Lise; Bichon, Emmanuelle; Guitton, Yann; Buisson, Corinne; Le Bizec, Bruno; Dervilly-Pinel, Gaud
      Metabolites (2019), 9 (12), 292CODEN: METALU; ISSN:2218-1989. (MDPI AG)
      Hydrophilic Interaction Liq. Chromatog. (HILIC) chromatog. is widely applied in metabolomics as a complementary strategy to reverse phase chromatog. Nevertheless, it still faces several issues in terms of peak shape and compds. ionization, limiting the automatic de-convolution and data semi-quantification performed through dedicated software. A way to improve the chromatog. and ionization performance of a HILIC method is to modify the electrostatic interactions of the analytes with both mobile and stationary phases. In this study, using a ZIC-HILIC chromatog. phase, we evaluated the performance of ammonium fluoride (AF) as additive salt, comparing its performance to ammonium acetate (AA). Three comparative criteria were selected: (1) identification and peak quality of 34 stds. following a metabolomics-specific evaluation approach, (2) an intraday repeatability test with real samples and (3) performing two real metabolomics fingerprints with the AF method to evaluate its inter-day repeatability. The AF method showed not only higher ionization efficiency and signal-to-noise ratio but also better repeatability and robustness than the AA approach. A tips and tricks section is then added, aiming at improving method replicability for further users. In conclusion, ammonium fluoride as additive salt presents several advantages and might be considered as a step forward in the application of robust HILIC methods in metabolomics.
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    34. 34
      Galvez, L.; Rusz, M.; Schwaiger-Haber, M. Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics. Metallomics 2019, 11, 1716– 1728,  DOI: 10.1039/c9mt00141g
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      Preclinical studies on metal based anticancer drugs as enabled by integrated metallomics and metabolomics
      Galvez, Luis; Rusz, Mate; Schwaiger-Haber, Michaela; El Abiead, Yasin; Hermann, Gerrit; Jungwirth, Ute; Berger, Walter; Keppler, Bernhard K.; Jakupec, Michael A.; Koellensperger, Gunda
      Metallomics (2019), 11 (10), 1716-1728CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)
      In this work we introduce a novel -omics workflow enabling the parallel study of platinum drug uptake and its distribution between nucleus/protein and small mol. fraction along with metabolic changes after different treatment time points. This integrated metallomics/metabolomics approach is facilitated by a tailored sample prepn. workflow suitable for preclin. studies on adherent cancer cell models. Inductively coupled plasma mass spectrometry monitors the platinum drug, while the metabolomics tool-set is provided by hydrophilic interaction liq. chromatog. combined with high-resoln. Orbitrap mass spectrometry. The implemented method covers biochem. key pathways of cancer cell metab. as shown by a panel of >130 metabolite stds. Furthermore, the addn. of yeast-based 13C-enriched internal stds. upon extn. enabled a novel targeted/untargeted anal. strategy. In this study we used our method to compare an oxaliplatin sensitive human colon cancer cell line (HCT116) and its corresponding resistant model. In the acquired oxaliplatin resistant cells distinct differences in oxaliplatin accumulation correlated with differences in metabolomic rearrangements. Using this multi-omics approach for platinum-treated samples facilitates the generation of novel hypotheses regarding the susceptibility and resistance towards oxaliplatin.
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    35. 35
      Koelmel, J. P.; Kroeger, N. M.; Gill, E. L. Expanding lipidome coverage using LC-MS/MS data-dependent acquisition with automated exclusion list generation. J. Am. Soc. Mass Spectrom. 2017, 28, 908– 917,  DOI: 10.1007/s13361-017-1608-0
      34
      Expanding Lipidome Coverage Using LC-MS/MS Data-Dependent Acquisition with Automated Exclusion List Generation
      Koelmel, Jeremy P.; Kroeger, Nicholas M.; Gill, Emily L.; Ulmer, Candice Z.; Bowden, John A.; Patterson, Rainey E.; Yost, Richard A.; Garrett, Timothy J.
      Journal of the American Society for Mass Spectrometry (2017), 28 (5), 908-917CODEN: JAMSEF; ISSN:1044-0305. (Springer)
      Untargeted omics analyses aim to comprehensively characterize biomols. within a biol. system. Changes in the presence or quantity of these biomols. can indicate important biol. perturbations, such as those caused by disease. With current technol. advancements, the entire genome can now be sequenced; however, in the burgeoning fields of lipidomics, only a subset of lipids can be identified. The recent emergence of high resoln. tandem mass spectrometry (HR-MS/MS), in combination with ultra-high performance liq. chromatog., has resulted in an increased coverage of the lipidome. Nevertheless, identifications from MS/MS are generally limited by the no. of precursors that can be selected for fragmentation during chromatog. elution. Therefore, we developed the software IE-Omics to automate iterative exclusion (IE), where selected precursors using data-dependent topN analyses are excluded in sequential injections. In each sequential injection, unique precursors are fragmented until HR-MS/MS spectra of all ions above a user-defined intensity threshold are acquired. IE-Omics was applied to lipidomics analyses in Red Cross plasma and substantia nigra tissue. Coverage of the lipidome was drastically improved using IE. When applying IE-Omics to Red Cross plasma and substantia nigra lipid exts. in pos. ion mode, 69% and 40% more mol. identifications were obtained, resp. In addn., applying IE-Omics to a lipidomics workflow increased the coverage of trace species, including odd-chained and short-chained diacylglycerides and oxidized lipid species. By increasing the coverage of the lipidome, applying IE to a lipidomics workflow increases the probability of finding biomarkers and provides addnl. information for detg. etiol. of disease.
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    36. 36
      MacLean, B.; Tomazela, D. M.; Shulman, N. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 2010, 26, 966– 968,  DOI: 10.1093/bioinformatics/btq054
      35
      Skyline: an open source document editor for creating and analyzing targeted proteomics experiments
      MacLean, Brendan; Tomazela, Daniela M.; Shulman, Nicholas; Chambers, Matthew; Finney, Gregory L.; Frewen, Barbara; Kern, Randall; Tabb, David L.; Liebler, Daniel C.; MacCoss, Michael J.
      Bioinformatics (2010), 26 (7), 966-968CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
      Summary: Skyline is a Windows client application for targeted proteomics method creation and quant. data anal. It is open source and freely available for academic and com. use. The Skyline user interface simplifies the development of mass spectrometer methods and the anal. of data from targeted proteomics expts. performed using selected reaction monitoring (SRM). Skyline supports using and creating MS/MS spectral libraries from a wide variety of sources to choose SRM filters and verify results based on previously obsd. ion trap data. Skyline exports transition lists to and imports the native output files from Agilent, Applied Biosystems, Thermo Fisher Scientific and Waters triple quadrupole instruments, seamlessly connecting mass spectrometer output back to the exptl. design document. The fast and compact Skyline file format is easily shared, even for expts. requiring many sample injections. A rich array of graphs displays results and provides powerful tools for inspecting data integrity as data are acquired, helping instrument operators to identify problems early. The Skyline dynamic report designer exports tabular data from the Skyline document model for in-depth anal. with common statistical tools. Availability: Single-click, self-updating web installation is available at http://proteome.gs.washington.edu/software/skyline. This web site also provides access to instructional videos, a support board, an issues list and a link to the source code project.
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    37. 37
      Ellison, SLR.; William, A. EURACHEM/CITAC Guide CG 4-Quantifying Uncertainty in Analytical Measurement, 3rd ed.; 2012.
      There is no corresponding record for this reference.
    38. 38
      Wei, T.; Simko, V. R package ″corrplot″: Visualization of a Correlation Matrix. 2017, https://githubcom/taiyun/corrplot (accessed April 11, 2022).
      There is no corresponding record for this reference.
    39. 39
      Pang, Z.; Chong, J.; Zhou, G.; de Lima Morais, D. A.; Chang, L.; Barrette, M.; Gauthier, C.; Jacques, P.-E.; Li, S.; Xia, J. MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 2021, 49, W388– W396,  DOI: 10.1093/nar/gkab382
      56
      MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights
      Pang, Zhiqiang; Chong, Jasmine; Zhou, Guangyan; Anderson de Lima Morais, David; Chang, Le; Barrette, Michel; Gauthier, Carol; Jacques, Pierre-Etienne; Li, Shuzhao; Xia, Jianguo
      Nucleic Acids Research (2021), 49 (W1), W388-W396CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
      Since its first release over a decade ago, the MetaboAnalyst web-based platform has become widely used for comprehensive metabolomics data anal. and interpretation. Here we introduce MetaboAnalyst version 5.0, aiming to narrow the gap from raw data to functional insights for global metabolomics based on high-resoln. mass spectrometry (HRMS). Three modules have been developed to help achieve this goal, including: (i) a LC-MS Spectra Processing module which offers an easy-to-use pipeline that can perform automated parameter optimization and resumable anal. to significantly lower the barriers to LC-MS1 spectra processing; (ii) a Functional Anal. module which expands the previous MS Peaks to Pathways module to allow users to intuitively select any peak groups of interest and evaluate their enrichment of potential functions as defined by metabolic pathways and metabolite sets; (iii) a Functional Meta-Anal. module to combine multiple global metabolomics datasets obtained under complementary conditions or from similar studies to arrive at comprehensive functional insights. There are many other new functions including weighted joint-pathway anal., data-driven network anal., batch effect correction, merging tech. replicates, improved compd. name matching, etc. The web interface, graphics and underlying codebase have also been refactored to improve performance and user experience. At the end of an anal. session, users can now easily switch to other compatible modules for a more streamlined data anal.
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    40. 40
      Helmus, R.; ter Laak, T. L.; van Wezel, A. P.; de Voogt, P.; Schymanski, E. L. patRoon: open source software platform for environmental mass spectrometry based non-target screening. J. Cheminf. 2021, 13, 1  DOI: 10.1186/s13321-020-00477-w
      38
      patRoon: open source software platform for environmental mass spectrometry based non-target screening
      Helmus, Rick; ter Laak, Thomas L.; van Wezel, Annemarie P.; de Voogt, Pim; Schymanski, Emma L.
      Journal of Cheminformatics (2021), 13 (1), 1CODEN: JCOHB3; ISSN:1758-2946. (SpringerOpen)
      Abstr.: Mass spectrometry based non-target anal. is increasingly adopted in environmental sciences to screen and identify numerous chems. simultaneously in highly complex samples. However, current data processing software either lack functionality for environmental sciences, solve only part of the workflow, are not openly available and/or are restricted in input data formats. In this paper we present patRoon, a new R based open-source software platform, which provides comprehensive, fully tailored and straightforward non-target anal. workflows. In addn., patRoon offers various functionality and strategies to simplify and perform automated processing of complex (environmental) data effectively. patRoon implements several effective optimization strategies to significantly reduce computational times. The ability of patRoon to perform time-efficient and automated non-target data annotation of environmental samples is demonstrated with a simple and reproducible workflow using open-access data of spiked samples from a drinking water treatment plant study. In addn., the ability to easily use, combine and evaluate different algorithms was demonstrated for three commonly used feature finding algorithms. This article, combined with already published works, demonstrate that patRoon helps make comprehensive (environmental) non-target anal. readily accessible to a wider community of researchers.
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    41. 41
      Chambers, M. C.; Maclean, B.; Burke, R. A cross-platform toolkit for mass spectrometry and proteomics. Nat. Biotechnol. 2012, 30, 918– 920,  DOI: 10.1038/nbt.2377
      39
      A cross-platform toolkit for mass spectrometry and proteomics
      Chambers, Matthew C.; MacLean, Brendan; Burke, Robert; Amodei, Dario; Ruderman, Daniel L.; Neumann, Steffen; Gatto, Laurent; Fischer, Bernd; Pratt, Brian; Egertson, Jarrett; Hoff, Katherine; Kessner, Darren; Tasman, Natalie; Shulman, Nicholas; Frewen, Barbara; Baker, Tahmina A.; Brusniak, Mi-Youn; Paulse, Christopher; Creasy, David; Flashner, Lisa; Kani, Kian; Moulding, Chris; Seymour, Sean L.; Nuwaysir, Lydia M.; Lefebvre, Brent; Kuhlmann, Frank; Roark, Joe; Rainer, Paape; Detlev, Suckau; Hemenway, Tina; Huhmer, Andreas; Langridge, James; Connolly, Brian; Chadick, Trey; Holly, Krisztina; Eckels, Josh; Deutsch, Eric W.; Moritz, Robert L.; Katz, Jonathan E.; Agus, David B.; MacCoss, Michael; Tabb, David L.; Mallick, Parag
      Nature Biotechnology (2012), 30 (10), 918-920CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      Mass spectrometry-based proteomics has become an important component of biol. research. There have been several calls for improvements and standardization of proteomics data anal. frameworks, as well as for an application programming interface for proteomics data access. In response, ProteoWizard Toolkit was developed, a robust set of opensource, software libraries and applications designed to facilitate proteomics research. With version 3.0 of the ProteoWizard Toolkit8, the challenges in the field can be mitigated through open-source, permissively licensed, cross-platform software. The Toolkit has two components: first, a suite of libraries that facilitate the development and comparison of tools for proteomics data anal. and second, a set of tools, developed using these libraries, that performs a wide array of common proteomics analyses. ProteoWizard is built upon a modular framework of many independent libraries grouped in dependency levels.
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    42. 42
      Sobus, J. R.; Grossman, J. N.; Chao, A. Using prepared mixtures of ToxCast chemicals to evaluate non-targeted analysis (NTA) method performance. Anal. Bioanal. Chem. 2019, 411, 835– 851,  DOI: 10.1007/s00216-018-1526-4
      40
      Using prepared mixtures of ToxCast chemicals to evaluate non-targeted analysis (NTA) method performance
      Sobus, Jon R.; Grossman, Jarod N.; Chao, Alex; Singh, Randolph; Williams, Antony J.; Grulke, Christopher M.; Richard, Ann M.; Newton, Seth R.; McEachran, Andrew D.; Ulrich, Elin M.
      Analytical and Bioanalytical Chemistry (2019), 411 (4), 835-851CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      Non-targeted anal. (NTA) methods are increasingly used to discover contaminants of emerging concern (CECs), but the extent to which these methods can support exposure and health studies remains to be detd.1416711539. EPA's Non-Targeted Anal. Collaborative Trial (ENTACT) was launched in 2016 to address this need. As part of ENTACT, 1269 unique substances from EPA's ToxCast library were combined to make ten synthetic mixts., with each mixt. contg. between 95 and 365 substances. As a participant in the trial, the authors first performed blinded NTA on each mixt. using liq. chromatog. (LC) coupled with high-resoln. mass spectrometry (HRMS). The authors then performed an unblinded evaluation to identify limitations of the authors' NTA method. Overall, at least 60% of spiked substances could be obsd. using selected methods. Discounting spiked isomers, true pos. rates from the blinded and unblinded analyses reached a max. of 46% and 65%, resp. An overall reproducibility rate of 75% was obsd. for substances spiked into more than one mixt. and obsd. at least once. Considerable discordance in substance identification was obsd. when comparing a subset of the authors' results derived from two sep. reversed-phase chromatog. methods. The authors conclude that a single NTA method, even when optimized, can likely characterize only a subset of ToxCast substances (and, by extension, other CECs). Rigorous quality control and self-evaluation practices should be required of labs generating NTA data to support exposure and health studies. Accurate and transparent communication of performance results will best enable meaningful interpretations and defensible use of NTA data. [Figure not available: see fulltext.].
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    43. 43
      Schymanski, E. L.; Jeon, J.; Gulde, R. Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence. Environ. Sci. Technol. 2014, 48, 2097– 2098,  DOI: 10.1021/es5002105
      41
      Identifying Small Molecules via High Resolution Mass Spectrometry: Communicating Confidence
      Schymanski, Emma L.; Jeon, Junho; Gulde, Rebekka; Fenner, Kathrin; Ruff, Matthias; Singer, Heinz P.; Hollender, Juliane
      Environmental Science & Technology (2014), 48 (4), 2097-2098CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      A method and framework for describing the identification of small mols. by high resoln. mass spectrometry (HRMS) is presented. A 5 level classification scheme was developed to indicate the proposed identification confidence levels in HRMS. The levels are confirmed structure, probable structure, substance class, unequivocal mol. formula, and exact mass of interest.
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    44. 44
      Karthikraj, R.; Lee, S.; Kannan, K. Biomonitoring of exposure to bisphenols, benzophenones, triclosan, and triclocarban in pet dogs and cats. Environ. Res. 2020, 180, 108821  DOI: 10.1016/j.envres.2019.108821
      42
      Biomonitoring of exposure to bisphenols, benzophenones, triclosan, and triclocarban in pet dogs and cats
      Karthikraj, Rajendiran; Lee, Sunmi; Kannan, Kurunthachalam
      Environmental Research (2020), 180 (), 108821CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
      Similar to humans, pet animals are exposed to environmental contaminants through multiple sources and pathways. Although a few studies have demonstrated exposure of cats and dogs to environmental chems., little is known about exposure to bisphenols, benzophenone UV filters, and antibacterial agents. In this study, we measured three bisphenols, three benzophenone-type UV filters, triclosan (TCS), and triclocarban (TCC) in dog (n = 50) and cat urine (n = 50) collected from New York State, USA. Among bisphenols, BPS was found at the highest concns. (mean ± SD: 3.2 ± 8.5 ng/mL in dogs and 8.85 ± 30.0 ng/mL in cats) with detection frequencies of 96% in dogs and 78% in cats. Among benzophenones, BP-3 (oxybenzone) was the dominant compd. in pet urine, followed by BP-1 and BP-8. TCS was found at concns. higher than those of TCC in both cat and dog urine. There were no significant differences in bisphenol concns. between sexes or age groups, both in dogs and cats. The calcd. hazard quotients (HQ) suggested that the current exposure levels of BPS and BP-3 in pets were 2-5 orders of magnitude below the tentative threshold values available for humans.
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    45. 45
      Zhu, H.; Chinthakindi, S.; Kannan, K. A method for the analysis of 121 multi-class environmental chemicals in urine by high-performance liquid chromatography-tandem mass spectrometry. J. Chromatogr. A 2021, 1646, 462146  DOI: 10.1016/j.chroma.2021.462146
      43
      A method for the analysis of 121 multi-class environmental chemicals in urine by high-performance liquid chromatography-tandem mass spectrometry
      Zhu, Hongkai; Chinthakindi, Sridhar; Kannan, Kurunthachalam
      Journal of Chromatography A (2021), 1646 (), 462146CODEN: JCRAEY; ISSN:0021-9673. (Elsevier B.V.)
      Biomonitoring of human exposure to environmental chems. has gained momentum in recent years. Biomonitoring methods often include anal. of a single class of chems. with similar chem. properties. In this study, we describe a method that involves solid-phase extn. (SPE) coupled with liq. chromatog.-tandem mass spectrometry (LC-MS/MS) and capable of measuring 121 environmental chems. comprising plasticizers (PMs; n = 45), environmental phenols (EPs; n = 45), and pesticides (n = 31) through a single extn. of urine. Urine samples were incubated with 20 μL of β-glucuronidase/arylsulfatase (4000 units/mL urine) (from Helix pomatia) buffered at pH 5.5 for 2 h at 37 °C for optimal deconjugation conditions. We compared two extn. methods, namely liq.-liq. extn. and SPE, and the latter with ABS Elut NEXUS cartridges was optimized to yield best extn. efficiencies. For increased resoln. and chromatog. sepn., two methods involving Ultra AQ C18 and Betasil C18 columns were used. The MS/MS analyses were performed under both neg. and pos. ionization modes. The optimized method yielded excellent intra- and inter-day variabilities (relative std. deviation: 0.40-11%) and satisfactory recoveries (80-120%) for >95% of the analytes. The limits of detection were ≤ 0.1 ng/mL for 101 analytes and between 0.1 and 1.0 ng/mL for 18 analytes. The optimized SPE LC-MS/MS method was validated through the anal. of std. ref. materials and proficiency test urine samples and further applied in the anal. of 21 real urine samples to demonstrate simultaneous detn. of 121 environmental chems. in urine samples.
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    46. 46
      Jiang, C.; Wang, X.; Li, X. Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring. Cell 2018, 175, 277– 291,  DOI: 10.1016/j.cell.2018.08.060
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      Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring
      Jiang, Chao; Wang, Xin; Li, Xiyan; Inlora, Jingga; Wang, Ting; Liu, Qing; Snyder, Michael
      Cell (Cambridge, MA, United States) (2018), 175 (1), 277-291.e31CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biol. and chem. exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geog. locations. We found that individuals are potentially exposed to thousands of pan-domain species and chem. compds., including insecticides and carcinogens. Personal biol. and chem. exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geog. region. Integrated anal. of biol. and chem. exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.
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    47. 47
      Ougier, E.; Zeman, F.; Antignac, J.-P. Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A. Environ. Int. 2021, 154, 106563  DOI: 10.1016/j.envint.2021.106563
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      Human biomonitoring initiative (HBM4EU): Human biomonitoring guidance values (HBM-GVs) derived for bisphenol A
      Ougier, Eva; Zeman, Florence; Antignac, Jean-Philippe; Rousselle, Christophe; Lange, Rosa; Kolossa-Gehring, Marike; Apel, Petra
      Environment International (2021), 154 (), 106563CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      A review. The "European Human Biomonitoring Initiative" (HBM4EU) derives human biomonitoring guidance values (HBM-GVs) for the general population (HBM-GVGenPop) and/or for occupationally exposed adults (HBM-GVWorker) for several priority substances and substance groups as identified by policy makers, scientists and stakeholders at EU and national level, including bisphenol A (BPA). Human exposure to BPA is widespread and of particular concern because of its known endocrine-disrupting properties. Unlike the conjugated forms of BPA circulating in the body, free BPA is known to interact with the nuclear estrogen receptors. Because free BPA is considered to be more toxicol. active than the conjugated forms (e.g. BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S)), its measurement in blood provides the superior surrogate of the biol. ED. However, considering the difficulty of implementing blood sampling in large HBM cohorts, as well as the current anal. capacities complying with the quality assurance (QA)/quality control (QC) schemes, total BPA in urine (i.e. the sum of free and conjugated forms of BPA measured after an hydrolysis of phase II metabolites) was retained as the relevant exposure biomarker for BPA. HBM-GVGenPop for total BPA in urine of 230μg/L and 135μg/L for adults and children, resp., were developed on the basis of toxicol. data. To derive these values, the concns. of urinary total BPA consistent with a steady-state exposure to the temporary Tolerable Daily Intake (t-TDI) of 4μg/kg bw/day set in 2015 by the European Food Safety Authority (EFSA) were estd. The BPA human physiol.-based pharmacokinetic (PBPK) model developed by Karrer et al. (2018) was used, assuming an oral exposure to BPA at the t-TDI level averaged over 24 h. Dermal uptake of BPA is suspected to contribute substantially to the total BPA body burden, which in comparison with the oral route, is generating a higher ratio of free BPA to total BPA in blood. Therefore, an alternative approach for calcg. the HBM-GVGenPop according to the estd. relative contributions of both the oral and dermal routes to the global BPA exposure is also discussed. Regarding BPA exposure at the workplace, the steady-state concn. of urinary total BPA was estd. after a dermal uptake of BPA that would generate the same concn. of free BPA in plasma (considered as the bioactive form) as would a 24 h-averaged intake to the European Chems. Agency (ECHA)'s oral DNEL of 8μg BPA/kg bw/day set for workers. The predicted concn. of urinary total BPA at steady-state is equiv. to, or exceeds the 95th percentile of total BPA in urine measured in different European HBM studies conducted in the general population. Thus, no HBM-GVWorker was proposed, as the high background level of BPA coming from environmental exposure - mostly through food intake - is making the discrimination with the occupational exposure to BPA difficult.
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    48. 48
      Wenzel, A. G.; Brock, J. W.; Cruze, L. Prevalence and predictors of phthalate exposure in pregnant women in Charleston, SC. Chemosphere 2018, 193, 394– 402,  DOI: 10.1016/j.chemosphere.2017.11.019
      46
      Prevalence and predictors of phthalate exposure in pregnant women in Charleston, SC
      Wenzel, Abby G.; Brock, John W.; Cruze, Lori; Newman, Roger B.; Unal, Elizabeth R.; Wolf, Bethany J.; Somerville, Stephen E.; Kucklick, John R.
      Chemosphere (2018), 193 (), 394-402CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)
      Phthalates are plasticizers commonly detected in human urine due to widespread exposure from PVC plastics, food packaging, and personal care products. We sampled urine from 378 pregnant women during the second trimester of gestation living in Charleston, SC, and measured eight urinary phthalate metabolites as biomarkers of phthalate exposure: monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), monoethyl phthalate (MEP), monoisobutyl phthalate (MiBP), and monomethyl phthalate (MMP). Demog. data was collected from questionnaires administered at the time of specimen collection. On av., concns. were highest for MEP (median = 47.0 ng/mL) and lowest for MMP (median = 1.92 ng/mL). Sociodemog. characteristics assocd. with elevated phthalate concns. included being unmarried, less educated, having a low income, high body mass index (BMI), and/or being African American. After racial stratification, age, BMI, education, and income were significantly assocd. with phthalate concns. in African American women. Marital status was assocd. with phthalate concns. in Caucasian women only, with greater concns. of MBP, MEHHP, MiBP, and MMP in unmarried vs. married women. Results of this cross-sectional study provide evidence for significant racial and demog. variations in phthalate exposure.
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    49. 49
      Axelson, M.; Sjövall, J.; Gustafsson, B. E.; Setchell, KDR. Origin of lignans in mammals and identification of a precursor from plants. Nature 1982, 298, 659– 660,  DOI: 10.1038/298659a0
      47
      Origin of lignans in mammals and identification of a precursor from plants
      Axelson, M.; Sjoevall, J.; Gustafsson, B. E.; Setchell, K. D. R.
      Nature (London, United Kingdom) (1982), 298 (5875), 659-60CODEN: NATUAS; ISSN:0028-0836.
      Evidence is presented which indicates that mammalian lignans are formed by microbial action on precursor lignans which are present as dietary constituents of plant origin. Precursors were found in seeds of different species, being particularly abundant in linseed. From this source 2,3-bis(3-methoxy-4-hydroxybenzyl)butane-1,4-diol (secoisolariciresinol) was identified as a glycoside.
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    50. 50
      Kang, H.; Kim, S.; Lee, G. Urinary metabolites of dibutyl phthalate and benzophenone-3 are potential chemical risk factors of chronic kidney function markers among healthy women. Environ. Int. 2019, 124, 354– 360,  DOI: 10.1016/j.envint.2019.01.028
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      Urinary metabolites of dibutyl phthalate and benzophenone-3 are potential chemical risk factors of chronic kidney function markers among healthy women
      Kang, Habyeong; Kim, Sunmi; Lee, Gowoon; Lee, Inae; Lee, Jung Pyo; Lee, Jeonghwan; Park, Hyunwoong; Moon, Hyo-Bang; Park, Jeongim; Kim, Sungkyoon; Choi, Gyuyeon; Choi, Kyungho
      Environment International (2019), 124 (), 354-360CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      Chronic kidney disease (CKD) is a global health threat of growing concern. Recently, exposure to endocrine disrupting compds. (EDCs) such as phthalates and bisphenol A has been suggested as a risk factor for CKD. However, most epidemiol. studies have focused on a limited no. of urinary chems. This study aimed to identify chem. determinants of the urinary albumin-to-creatinine ratio (ACR), which is a kidney function marker, among multiple major EDCs including phthalate metabolites, bisphenols, and benzophenones in a Korean female population (20-45 years old, n = 441). First, the creatinine-adjusted urinary concn. of each urinary chem. was assocd. with ACR in a linear regression model (single-pollutant model). Then, compds. with a significant assocn. with ACR in the single-pollutant model were added in a multi-pollutant model and evaluated for their assocn. with ACR. Moreover, to prevent potential reverse causality due to impaired kidney function, quartile analyses were performed for the subjects with healthy renal function (ACR < 9.71 mg/g). In addn. to creatinine adjustment, the statistical anal. was also conducted with sp. gr.-adjusted concns. of urinary chems., and the results were compared. Several compds. measured in the urine showed a significant assocn. with ACR in the single-pollutant model. In the multi-pollutant model, however, only monobutyl phthalate and benzophenone-1, which are metabolites of di-Bu phthalate and benzophenone-3, resp., showed significant pos. assocns. The assocn. of these chems. remained significant in a couple of the sensitivity analyses with a different adjustment of urine diln. and in a subpopulation with normal ACR. In conclusion, among dozens of urinary chems., monobutyl phthalate and benzophenone-1 consistently showed a strong assocn. with urinary ACR. Confirmation of our observation in other human populations and exptl. studies is warranted.
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    51. 51
      Wolff, M. S.; Teitelbaum, S. L.; McGovern, K. Environmental phenols and pubertal development in girls. Environ. Int. 2015, 84, 174– 180,  DOI: 10.1016/j.envint.2015.08.008
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      Environmental phenols and pubertal development in girls
      Wolff, Mary S.; Teitelbaum, Susan L.; McGovern, Kathleen; Pinney, Susan M.; Windham, Gayle C.; Galvez, Maida; Pajak, Ashley; Rybak, Michael; Calafat, Antonia M.; Kushi, Lawrence H.; Biro, Frank M.
      Environment International (2015), 84 (), 174-180CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      Environmental exposures to many phenols are documented worldwide and exposures can be quite high (> 1 μM of urine metabolites). Phenols have a range of hormonal activity, but knowledge of effects on child reproductive development is limited, coming mostly from cross-sectional studies. We undertook a prospective study of pubertal development among 1239 girls recruited at three U. S. sites when they were 6-8 years old and were followed annually for 7 years to det. age at first breast or pubic hair development. Ten phenols were measured in urine collected at enrollment (benzophenone-3, enterolactone, bisphenol A, three parabens (methyl-, ethyl-, propyl-), 2,5-dichlorophenol, triclosan, genistein, daidzein). We used multivariable adjusted Cox proportional hazards ratios (HR (95% confidence intervals)) and Kaplan-Meier survival analyses to est. relative risk of earlier or later age at puberty assocd. with phenol exposures. For enterolactone and benzophenone-3, girls experienced breast development 5-6 mo later, adjusted HR 0.79 (0.64-0.98) and HR 0.80 (0.65-0.98) resp. for the 5th vs 1st quintiles of urinary biomarkers (μg/g-creatinine). Earlier breast development was seen for triclosan and 2,5-dichlorophenol: 4-9 mo sooner for 5th vs 1st quintiles of urinary concns. (HR 1.17 (0.96-1.43) and HR 1.37 (1.09-1.72), resp.). Assocn. of breast development with enterolactone, but not the other three phenols, was mediated by body size. These phenols may be antiadipogens (benzophenone-3 and enterolactone) or thyroid agonists (triclosan and 2,5-dichlorophenol), and their ubiquity and relatively high levels in children would benefit from further investigation to confirm these findings and to establish whether there are certain windows of susceptibility during which exposure can affect pubertal development.
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    52. 52
      Zhang, J.; Liu, L.; Wang, X.; Huang, Q.; Tian, M.; Shen, H. Low-Level Environmental Phthalate Exposure Associates with Urine Metabolome Alteration in a Chinese Male Cohort. Environ. Sci. Technol. 2016, 50, 5953– 5960,  DOI: 10.1021/acs.est.6b00034
      50
      Low-Level Environmental Phthalate Exposure Associates with Urine Metabolome Alteration in a Chinese Male Cohort
      Zhang, Jie; Liu, Liangpo; Wang, Xiaofei; Huang, Qingyu; Tian, Meiping; Shen, Heqing
      Environmental Science & Technology (2016), 50 (11), 5953-5960CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)
      The general population is exposed to phthalates through various sources and routes. Integration of omics data and epidemiol. data is a key step toward directly linking phthalate biomonitoring data with biol. response. Urine metabolomics is a powerful tool to identify exposure biomarkers and delineate the modes of action of environmental stressors. The objectives of this study are to investigate the assocn. between low-level environmental phthalate exposure and urine metabolome alteration in male population, and to unveil the metabolic pathways involved in the mechanisms of phthalate toxicity. In this retrospective cross-sectional study, we studied the urine metabolomic profiles of 364 male subjects exposed to low-level environmental phthalates. Di(2-ethylhexyl) phthalate (DEHP) and di-Bu phthalate (DBP) are the most widely used phthalates. .sum.DEHP and MBP (the major metabolite of DBP) were assocd. with significant alteration of global urine metabolome in the male population. We obsd. significant increase in the levels of acetylneuraminic acid, carnitine C8:1, carnitine C18:0, cystine, phenylglycine, phenylpyruvic acid and glutamylphenylalanine; and meanwhile, decrease in the levels of carnitine C16:2, diacetylspermine, alanine, taurine, tryptophan, ornithine, methylglutaconic acid, hydroxyl-PEG2 and keto-PGE2 in high exposure group. The observations indicated that low-level environmental phthalate exposure assocd. with increased oxidative stress and fatty acid oxidn. and decreased prostaglandin metab. Urea cycle, tryptophan and phenylalanine metab. disruption was also obsd. The urine metabolome disruption effects assocd. with .sum.DEHP and MBP were similar, but not identical. The multibiomarker models presented AUC values of 0.845 and 0.834 for .sum.DEHP and MBP, resp. The predictive accuracy rates of established models were 81% for ΣDEHP and 73% for MBP. Our results suggest that low-level environmental phthalate exposure assocs. with urine metabolome disruption in male population, providing new insight into the early mol. events of phthalate exposure.
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    53. 53
      Tang, S.; Li, T.; Fang, J. The exposome in practice: an exploratory panel study of biomarkers of air pollutant exposure in Chinese people aged 60–69 years (China BAPE Study). Environ. Int. 2021, 157, 106866  DOI: 10.1016/j.envint.2021.106866
      51
      The exposome in practice: an exploratory panel study of biomarkers of air pollutant exposure in Chinese people aged 60-69 years (China BAPE Study)
      Tang, Song; Li, Tiantian; Fang, Jianlong; Chen, Renjie; Cha, Yu'e; Wang, Yanwen; Zhu, Mu; Zhang, Yi; Chen, Yuanyuan; Du, Yanjun; Yu, Tianwei; Thompson, David C.; Godri Pollitt, Krystal J.; Vasiliou, Vasilis; Ji, John S.; Kan, Haidong; Zhang, Junfeng Jim; Shi, Xiaoming
      Environment International (2021), 157 (), 106866CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      The exposome overhauls conventional environmental health impact research paradigms and provides a novel methodol. framework that comprehensively addresses the complex, highly dynamic interplays of exogenous exposures, endogenous exposures, and modifiable factors in humans. Holistic assessments of the adverse health effects and systematic elucidation of the mechanisms underlying environmental exposures are major scientific challenges with widespread societal implications. However, to date, few studies have comprehensively and simultaneously measured airborne pollutant exposures and explored the assocd. biomarkers in susceptible healthy elderly subjects, potentially resulting in the suboptimal assessment and management of health risks. To demonstrate the exposome paradigm, we describe the rationale and design of a comprehensive biomarker and biomonitoring panel study to systematically explore the assocn. between individual airborne exposure and adverse health outcomes. We used a combination of personal monitoring for airborne pollutants, extensive human biomonitoring, advanced omics anal., confounding information, and statistical methods. We established an exploratory panel study of Biomarkers of Air Pollutant Exposure in Chinese people aged 60-69 years (China BAPE), which included 76 healthy residents from a representative community in Jinan City, Shandong Province. During the period between Sept. 2018 and Jan. 2019, we conducted prospective longitudinal monitoring with a 3-day assessment every month. This project: (1) leveraged advanced tools for personal airborne exposure monitoring (external exposures); (2) comprehensively characterized biol. samples for exogenous and endogenous compds. (e.g., targeted and untargeted monitoring) and multi-omics scale measurements to explore potential biomarkers and putative toxicity pathways; and (3) systematically evaluated the relationships between personal exposure to air pollutants, and novel biomarkers of exposures and effects using exposome-wide assocn. study approaches. These findings will contribute to our understanding of the mechanisms underlying the adverse health impacts of air pollution exposures and identify potential adverse clin. outcomes that can facilitate the development of effective prevention and targeted intervention techniques.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitVajsb7F&md5=a652afec0860235f93e5a627ff7f0a9f
    54. 54
      Alderete, T. L.; Jin, R.; Walker, D. I. Perfluoroalkyl substances, metabolomic profiling, and alterations in glucose homeostasis among overweight and obese Hispanic children: A proof-of-concept analysis. Environ. Int. 2019, 126, 445– 453,  DOI: 10.1016/j.envint.2019.02.047
      52
      Perfluoroalkyl substances, metabolomic profiling, and alterations in glucose homeostasis among overweight and obese Hispanic children: A proof-of-concept analysis
      Alderete, Tanya L.; Jin, Ran; Walker, Douglas I.; Valvi, Damaskini; Chen, Zhanghua; Jones, Dean P.; Peng, Cheng; Gilliland, Frank D.; Berhane, Kiros; Conti, David V.; Goran, Michael I.; Chatzi, Lida
      Environment International (2019), 126 (), 445-453CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)
      To examine the prospective assocns. between exposure to perfluoroalkyl substances (PFASs) and longitudinal measurements of glucose metab. in high-risk overweight and obese Hispanic children. Forty overweight and obese Hispanic children (8-14 years) from urban Los Angeles underwent clin. measures and 2-h oral glucose tolerance tests (OGTT) at baseline and a follow-up visit (range: 1-3 years after enrollment). Baseline plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and the plasma metabolome were measured by liq.-chromatog. with high-resoln. mass spectrometry. Multiple linear regression models were used to assess the assocn. between baseline PFASs and changes in glucose homeostasis over follow-up. A metabolome-wide assocn. study coupled with pathway enrichment anal. was performed to evaluate metabolic dysregulation assocd. with plasma PFASs concns. We performed a structural integrated anal. aiming to characterize the joint impact of all factors and to identify latent clusters of children with alterations in glucose homeostasis, based on their exposure and metabolomics profile. Each ln (ng/mL) increase in PFOA and PFHxS concns. was assocd. with a 30.6 mg/dL (95% CI: 8.8-52.4) and 10.2 mg/dL (95% CI: 2.7-17.7) increase in 2-h glucose levels, resp. A ln (ng/mL) increase in PFHxS concns. was also assocd. with 17.8 mg/dL increase in the glucose area under the curve (95% CI: 1.5-34.1). Pathway enrichment anal. showed significant alterations of lipids (e.g., glycosphingolipids, linoleic acid, and de novo lipogenesis), and amino acids (e.g., aspartate and asparagine, tyrosine, arginine and proline) in assocn. to PFASs exposure. The integrated anal. identified a cluster of children with increased 2-h glucose levels over follow up, characterized by increased PFAS levels and altered metabolite patterns. This proof-of-concept anal. shows that higher PFAS exposure was assocd. with dysregulation of several lipid and amino acid pathways and longitudinal alterations in glucose homeostasis in Hispanic youth. Larger studies are needed to confirm these findings and fully elucidate the underlying biol. mechanisms.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXkt1WktL4%253D&md5=da0507754864fd88e6b29b6cca041fed
    55. 55
      Ulrich, E. M.; Sobus, J. R.; Grulke, C. M. EPA’s non-targeted analysis collaborative trial (ENTACT): genesis, design, and initial findings. Anal. Bioanal. Chem. 2019, 411, 853– 866,  DOI: 10.1007/s00216-018-1435-6
      53
      EPA's non-targeted analysis collaborative trial (ENTACT): genesis, design, and initial findings
      Ulrich, Elin M.; Sobus, Jon R.; Grulke, Christopher M.; Richard, Ann M.; Newton, Seth R.; Strynar, Mark J.; Mansouri, Kamel; Williams, Antony J.
      Analytical and Bioanalytical Chemistry (2019), 411 (4), 853-866CODEN: ABCNBP; ISSN:1618-2642. (Springer)
      In August 2015, the US Environmental Protection Agency (EPA) convened a workshop entitled "Advancing non-targeted analyses of xenobiotic chems. in environmental and biol. media.". The purpose of the workshop was to bring together the foremost experts in non-targeted anal. (NTA) to discuss the state-of-the-science for generating, interpreting, and exchanging NTA measurement data. During the workshop, participants discussed potential designs for a collaborative project that would use EPA resources, including the ToxCast library of chem. substances, the DSSTox database, and the CompTox Chems. Dashboard, to evaluate cutting-edge NTA methods. That discussion was the genesis of EPA's Non-Targeted Anal. Collaborative Trial (ENTACT). Nearly 30 labs. have enrolled in ENTACT and used a variety of chromatog., mass spectrometry, and data processing approaches to characterize ten synthetic chem. mixts., three standardized media (human serum, house dust, and silicone band) exts., and thousands of individual substances. Initial results show that nearly all participants have detected and reported more compds. in the mixts. than were intentionally added, with large inter-lab variability in the no. of reported compds. A comparison of gas and liq. chromatog. results shows that the majority (45.3%) of correctly identified compds. were detected by only one method and 15.4% of compds. were not identified. Finally, a limited set of true pos. identifications indicates substantial differences in observable chem. space when employing disparate sepn. and ionization techniques as part of NTA workflows. This article describes the genesis of ENTACT, all study methods and materials, and an anal. of results submitted to date. [Figure not available: see fulltext.].
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisVemtr7F&md5=623fd946647f9c28fb6d30e901da726b
    56. 56
      Hu, Y.; Cai, B.; Huan, T. Enhancing Metabolome Coverage in Data-Dependent LC–MS/MS Analysis through an Integrated Feature Extraction Strategy. Anal. Chem. 2019,  DOI: 10.1021/acs.analchem.9b02980
      There is no corresponding record for this reference.

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.2c00433.

    • Supporting Information A: visualization of the diversity of selected model molecules, normalized peak areas of QC samples, concentrations of noncertified values in the reference material, Spearman correlation matrix, summary of detected xenobiotics in Austrian urine samples, pathway analyses, total ion chromatograms, summary of molecules in a multi-analyte mixture and their concentrations including internal standards, average peak areas of analytes for different eluent/column combinations, limits of detection and retention times of analytes, calibration parameters, and linear dynamic ranges and recoveries of analytes (PDF)

    • Supporting Information B: detailed results of Nigerian and Austrian urine analysis, concentrations of certified values in reference materials, results of suspect screening approach, creatinine levels of urine samples, selected extracted ion chromatograms, quality control charts, PCA plots, and peak areas of pooled QC sample over several injections (XLSX)


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