Electronic Cigarette Solvents, JUUL E-Liquids, and Biomarkers of Exposure: In Vivo Evidence for Acrolein and Glycidol in E-Cig-Derived Aerosols

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

This article references 43 other publications.

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   Bhatnagar, Aruni

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   Environmental factors are considered key determinants of cardiovascular disease. Although lifestyle choices such as smoking, diet, and exercise are viewed as major environmental influences, the contribution of pollutants and environmental chems. is less clear. Accumulating evidence suggests that exposure to pollutants and chems. could elevate the risk of cardiovascular disease. Many epidemiol. studies report that exposure to fine particles present in ambient air is assocd. with an increase in cardiovascular mortality. Statistically significant relationships between particulate air pollution and ischemic heart disease, arrhythmias, and heart failure have been reported. Animal studies show that exposure to ambient air particles increases peripheral thrombosis and atherosclerotic lesion formation. Exposures to arsenic, lead, cadmium, pollutant gases, solvents, and pesticides have also been linked to increased incidence of cardiovascular disease. Mechanistically, these effects have been attributed to changes in the synthesis or reactivity of nitric oxide that may be caused by environmental oxidants or increased endogenous prodn. of reactive oxygen species. Addnl. studies are urgently needed to: identify the contribution of individual pollutants to specific aspects of cardiovascular disease; establish causality; elucidate the underlying physiol. and mol. mechanisms; est. the relative susceptibility of diseased and healthy individuals and that of specific population groups; and det. whether pollutant exposure are risk correlates, i.e., whether they influence major risk factors, such as hypertension, cholesterol, or diabetes, or whether they contribute to the abs. risk of heart disease. Collectively, these investigations could contribute to the emergent field of environmental cardiol.

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   A review. Cigarette smoking (CS) continues to be a major health hazard, and it contributes significantly to cardiovascular morbidity and mortality. Cigarette smoking impacts all phases of atherosclerosis from endothelial dysfunction to acute clin. events, the latter being largely thrombotic. Both active and passive (environmental) cigarette smoke exposure predispose to cardiovascular events. Whether there is a distinct direct dose-dependent correlation between cigarette smoke exposure and risk is debatable, as some recent exptl. clin. studies have shown a nonlinear relation to cigarette smoke exposure. The exact toxic components of cigarette smoke and the mechanisms involved in CS-related cardiovascular dysfunction are largely unknown, but CS increases inflammation, thrombosis, and oxidn. of low-d. lipoprotein cholesterol. Recent exptl. and clin. data support the hypothesis that cigarette smoke exposure increases oxidative stress as a potential mechanism for initiating cardiovascular dysfunction.

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   Cardiorespiratory and Immunologic Effects of Electronic Cigarettes

   Keith Rachel; Bhatnagar Aruni

   Current addiction reports (2021), (), 1-11 ISSN:2196-2952.

   Purpose of Review: Although e-cigarettes have become popular, especially among youth, the health effects associated with e-cigarette use remain unclear. This review discusses current evidence relating to the cardiovascular, pulmonary, and immunological effects of e-cigarettes. Recent Findings: The use of e-cigarettes by healthy adults has been shown to increase blood pressure, heart rate, and arterial stiffness, as well as resistance to air flow in lungs. Inhalation of e-cigarette aerosol has been shown to elicit immune responses and increase the production of immunomodulatory cytokines in young tobacco-naive individuals. In animal models, long-term exposure to e-cigarettes leads to marked changes in lung architecture, dysregulation of immune genes, and low-grade inflammation. Exposure to e-cigarette aerosols in mice has been shown to induce DNA damage, inhibit DNA repair, and promote carcinogenesis. Chronic exposure to e-cigarettes has also been reported to result in the accumulation of lipid-laden macrophages in the lung and dysregulation of lipid metabolism and transport in mice. Although, the genotoxic and inflammatory effects of e-cigarettes are milder than those of combustible cigarettes, some of the cardiorespiratory effects of the two insults are comparable. The toxicity of e-cigarettes has been variably linked to nicotine, as well as other e-cigarette constituents, operating conditions, and use patterns. Summary: The use of e-cigarettes in humans is associated with significant adverse cardiorespiratory and immunological changes. Data from animal models and in vitro studies support the notion that long-term use of e-cigarettes may pose significant health risks.

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   Gas chromatography-mass spectrometry of carbonyl compounds in cigarette mainstream smoke after derivatization with 2,4-dinitrophenylhydrazine

   Dong, Ji-Zhou; Moldoveanu, Serban C.

   Journal of Chromatography A (2004), 1027 (1-2), 25-35CODEN: JCRAEY; ISSN:0021-9673. (Elsevier Science B.V.)

   An improved gas chromatog.-mass spectrometry (GC-MS) method was described for the anal. of carbonyl compds. in cigarette mainstream smoke (CMS) after 2,4-dinitrophenylhydrazine (DNPH) derivatization. Besides formaldehyde, acetaldehyde, acetone, acrolein, propionaldehyde, Me Et ketone, butyraldehyde, and crotonaldehyde that are routinely analyzed in cigarette smoke, this technique separates and allows the anal. of several C4, C5 and C6 isomeric carbonyl compds. Differentiation could be made between the linear and branched carbon chain components. In cigarette smoke, the branched chain carbonyls are found at higher level than the linear chain carbonyls. Also, several trace carbonyl compds. such as methoxyacetaldehyde were found for the first time in cigarette smoke. For the anal., cigarette smoke was collected using DNPH-treated pads, which is a simpler procedure compared to conventional impinger collection. Thermal decompn. of DNPH-carbonyl compds. was minimized by the optimization of the GC conditions. The linear range of the method was significantly improved by using a std. mixt. of DNPH-carbonyl compds. instead of individual compds. for calibration. The min. detectable quantity for the carbonyls ranged from 1.4 to 5.6 μg/cigarette.

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    Jaccard, G.; Djoko, D. T.; Korneliou, A.; Stabbert, R.; Belushkin, M.; Esposito, M. Mainstream smoke constituents and in vitro toxicity comparative analysis of 3R4F and 1R6F reference cigarettes. Toxicol. Rep. 2019, 6, 222– 231,  DOI: 10.1016/j.toxrep.2019.02.009

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    Jaccard, Guy; Djoko, Donatien Tafin; Korneliou, Alexandra; Stabbert, Regina; Belushkin, Maxim; Esposito, Marco

    Toxicology Reports (2019), 6 (), 222-231CODEN: TROEF9; ISSN:2214-7500. (Elsevier B.V.)

    A new Kentucky ref. cigarette, 1R6F, has been manufd. to replace the depleting 3R4F ref. cigarette. The 3R4F Kentucky ref. cigarettes have been widely used as monitor or comparator cigarettes for mainstream smoke anal. and in vitro and in vivo toxicol. data of cigarettes and novel tobacco products. Both ref. cigarettes were analyzed in the same lab. during the same period of time with the goal of performing a comparison of 3R4F and 1R6F. On the basis of the results obtained from aerosol chem. and in vitro assays, we consider that the 1R6F ref. cigarette is a suitable replacement for the 3R4F ref. cigarette as a comparator/monitor cigarette. Its specific use as a comparator for novel tobacco products was checked on the basis of a comparative test with the Tobacco Heating System 2.2 as an example.

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    Use of hazard indices for a theoretical evaluation of cigarette smoke composition

    Haussmann, Hans-Juergen

    Chemical Research in Toxicology (2012), 25 (4), 794-810CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)

    A review. The chem. compn. of cigarette mainstream smoke (MS) has been quant. analyzed in multiple studies, often with the objective to toxicol. evaluate and compare various types of MS. Increases and decreases in yields of constituents between MS types can only be consolidated if these yields are compared on the basis of toxicol. properties of the individual constituents. For the risk assessment of various complex mixts. including MS, a hazard index (HI) approach has been used that requires weighing of the exposure to individual MS constituents by cancer and noncancer potency values. The objective of the current study is to review the past uses of the HI concept for MS and smokeless tobacco and discuss strengths and limitations of using this concept. Published information as well as information made available on the Web was used. The HI concept has been applied to MS for detg. and comparing theor. lifetime risks, for consumer communication, for the prioritization of constituents for redn., for ingredient assessment, and for the selection of constituents for regulation. The limitations of this approach are assocd. with the limited no. of MS constituents with available yield data, the gaps and uncertainties in available potency values, the application to relatively high exposure concns., and the default assumption of additivity. The derived theor. noncancer index is dominated by acrolein to an extent that there seems to be not much advantage in using the HI concept for noncancer assessments. The derived theor. cancer index is dominated by genotoxic carcinogens of the MS vapor phase and may thus complement currently used toxicol. assays in a tiered evaluation approach. As is the case for every other assay and interpretation model, the HI concept needs to be applied with its limitations and weaknesses in mind. Its best application is for comparative purposes. It should be kept in mind that the HI concept is a theor. concept and does not provide actual risk information.

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    Kosmider, L.; Sobczak, A.; Fik, M.; Knysak, J.; Zaciera, M.; Kurek, J.; Goniewicz, M. L. Carbonyl compounds in electronic cigarette vapors-effects of nicotine solvent and battery output voltage. Nicotine Tob. Res. 2014, 16, 1319– 1326,  DOI: 10.1093/ntr/ntu078

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    Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltage

    Kosmider, Leon; Sobczak, Andrzej; Fik, Maciej; Knysak, Jakub; Zaciera, Marzena; Kurek, Jolanta; Goniewicz, Maciej Lukasz

    Nicotine & Tobacco Research (2014), 16 (10), 1319-1326CODEN: NTREF6; ISSN:1462-2203. (Oxford University Press)

    Introduction: Glycerin (VG) and propylene glycol (PG) are the most common nicotine solvents used in e-cigarettes (ECs). It has been shown that at high temps. both VG and PG undergo decompn. to low mol. carbonyl compds., including the carcinogens formaldehyde and acetaldehyde. The aim of this study was to evaluate how various product characteristics, including nicotine solvent and battery output voltage, affect the levels of carbonyls in EC vapor. Methods: Twelve carbonyl compds. were measured in vapors from 10 com. available nicotine solns. and from 3 control solns. composed of pure glycerin, pure propylene glycol, or a mixt. of both solvents (50:50). EC battery output voltage was gradually modified from 3.2 to 4.8 V. Carbonyl compds. were detd. using the HPLC/DAD method. Results: Formaldehyde and acetaldehyde were found in 8 of 13 samples. The amts. of formaldehyde and acetaldehyde in vapors from lower voltage EC were on av. 13- and 807-fold lower than in tobacco smoke, resp. The highest levels of carbonyls were obsd. in vapors generated from PG-based solns. Increasing voltage from 3.2 to 4.8 V resulted in a 4 to more than 200 times increase in formaldehyde, acetaldehyde, and acetone levels. The levels of formaldehyde in vapors from high-voltage device were in the range of levels reported in tobacco smoke. Conclusions: Vapors from EC contain toxic and carcinogenic carbonyl compds. Both solvent and battery output voltage significantly affect levels of carbonyl compds. in EC vapors. High-voltage EC may expose users to high levels of carbonyl compds.

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    Talih, S.; Balhas, Z.; Eissenberg, T.; Salman, R.; Karaoghlanian, N.; El Hellani, A.; Baalbaki, R.; Saliba, N.; Shihadeh, A. Effects of user puff topography, device voltage, and liquid nicotine concentration on electronic cigarette nicotine yield: measurements and model predictions. Nicotine Tob. Res. 2015, 17, 150– 157,  DOI: 10.1093/ntr/ntu174

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    Effects of user puff topography, device voltage, and liquid nicotine concentration on electronic cigarette nicotine yield: measurements and model predictions

    Talih, Soha; Balhas, Zainab; Eissenberg, Thomas; Salman, Rola; Karaoghlanian, Nareg; El Hellani, Ahmad; Baalbaki, Rima; Saliba, Najat; Shihadeh, Alan

    Nicotine & Tobacco Research (2015), 17 (2), 150-157CODEN: NTREF6; ISSN:1462-2203. (Oxford University Press)

    Introduction: Some electronic cigarette (ECIG) users attain tobacco cigarette-like plasma nicotine concns. while others do not. Understanding the factors that influence ECIG aerosol nicotine delivery is relevant to regulation, including product labeling and abuse liability. These factors may include user puff topog., ECIG liq. compn., and ECIG design features. This study addresses how these factors can influence ECIG nicotine yield. Methods: Aerosols were machine generated with 1 type of ECIG cartridge (V4L CoolCart) using 5 distinct puff profiles representing a tobacco cigarette smoker (2-s puff duration, 33-mL/s puff velocity), a slow av. ECIG user (4 s, 17 mL/s), a fast av. user (4 s, 33 mL/s), a slow extreme user (8 s, 17 mL/s), and a fast extreme user (8 s, 33 mL/s). Output voltage (3.3-5.2 V or 3.0-7.5 W) and e-liq. nicotine concn. (18-36 mg/mL labeled concn.) were varied. A theor. model was also developed to simulate the ECIG aerosol prodn. process and to provide insight into the empirical observations. Results: Nicotine yields from 15 puffs varied by more than 50-fold across conditions. Experienced ECIG user profiles (longer puffs) resulted in higher nicotine yields relative to the tobacco smoker (shorter puffs). Puff velocity had no effect on nicotine yield. Higher nicotine concn. and higher voltages resulted in higher nicotine yields. These results were predicted well by the theor. model (R2 = 0.99). Conclusions: Depending on puff conditions and product features, 15 puffs from an ECIG can provide far less or far more nicotine than a single tobacco cigarette. ECIG emissions can be predicted using phys. principles, with knowledge of puff topog. and a few ECIG device design parameters.

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    Geiss, O.; Bianchi, I.; Barrero-Moreno, J. Correlation of volatile carbonyl yields emitted by e-cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours. Int. J. Hyg. Environ. Health 2016, 219, 268– 277,  DOI: 10.1016/j.ijheh.2016.01.004

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    Correlation of volatile carbonyl yields emitted by e-cigarettes with the temperature of the heating coil and the perceived sensorial quality of the generated vapours

    Geiss, Otmar; Bianchi, Ivana; Barrero-Moreno, Josefa

    International Journal of Hygiene and Environmental Health (2016), 219 (3), 268-277CODEN: IJEHFT; ISSN:1438-4639. (Elsevier GmbH)

    E-liqs. generally contain four main components: nicotine, flavours, water and carrier liqs. The carrier liq. dissolves flavours and nicotine and vaporises at a certain temp. on the atomizer of the e-cigarette. Propylene glycol and glycerol, the principal carriers used in e-liqs., undergo decompn. in contact with the atomizer heating-coil forming volatile carbonyls. Some of these, such as formaldehyde, acetaldehyde and acrolein, are of concern due to their adverse impact on human health when inhaled at sufficient concns. The aim of this study was to correlate the yield of volatile carbonyls emitted by e-cigarettes with the temp. of the heating coil.For this purpose, a popular com. e-liq. was machine-vaped on a third generation e-cigarette which allowed the variation of the output wattage (5-25 W) and therefore the heat generated on the atomizer heating-coil. The temp. of the heating-coil was detd. by IR thermog. and the vapor generated at each temp. underwent subjective sensorial quality evaluation by an experienced vaper.A steep increase in the generated carbonyls was obsd. when applying a battery-output of at least 15 W corresponding to 200-250 °C on the heating coil. However, when considering concns. in each inhaled puff, the short-term indoor air guideline value for formaldehyde was already exceeded at the lowest wattage of 5 W, which is the wattage applied in most 2nd generation e-cigarettes. Concns. of acetaldehyde in each puff were several times below the short-term irritation threshold value for humans. Acrolein was only detected from 20 W upwards. The neg. sensorial quality evaluation by the volunteering vaper of the vapor generated at 20 W demonstrated the unlikelihood that such a wattage would be realistically set by a vaper. This study highlights the importance to develop standardised testing methods for the assessment of carbonyl-emissions and emissions of other potentially harmful compds. from e-cigarettes. The wide variety and variability of products available on the market make the development of such methods and the assocd. standardised testing conditions particularly demanding.

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15. 15

    Gillman, I. G.; Kistler, K. A.; Stewart, E. W.; Paolantonio, A. R. Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e-cigarette aerosols. Regul. Toxicol. Pharmacol. 2016, 75, 58– 65,  DOI: 10.1016/j.yrtph.2015.12.019

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    Effect of variable power levels on the yield of total aerosol mass and formation of aldehydes in e-cigarette aerosols

    Gillman, I. G.; Kistler, K. A.; Stewart, E. W.; Paolantonio, A. R.

    Regulatory Toxicology and Pharmacology (2016), 75 (), 58-65CODEN: RTOPDW; ISSN:0273-2300. (Elsevier Inc.)

    The study objective was to det. the effect of variable power applied to the atomizer of refillable tank based e-cigarette (EC) devices. Five different devices were evaluated, each at four power levels. Aerosol yield results are reported for each set of 25 EC puffs, as mass/puff, and normalized for the power applied to the coil, in mass/W. The range of aerosol produced on a per puff basis ranged from 1.5 to 28 mg, and, normalized for power applied to the coil, ranged from 0.27 to 1.1 mg/W. Aerosol samples were also analyzed for the prodn. of formaldehyde, acetaldehyde, and acrolein, as DNPH derivs., at each power level. When reported on mass basis, three of the devices showed an increase in total aldehyde yield with increasing power applied to the coil, while two of the devices showed the opposite trend. The mass of formaldehyde, acetaldehyde, and acrolein produced per g of total aerosol produced ranged from 0.01 to 7.3 mg/g, 0.006 to 5.8 mg/g, and <0.003 to 0.78 mg/g, resp. These results were used to est. daily exposure to formaldehyde, acetaldehyde, and acrolein from EC aerosols from specific devices, and were compared to estd. exposure from consumption of cigarettes, to occupational and workplace limits, and to previously reported results from other researchers.

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16. 16

    Ogunwale, M. A.; Li, M.; Ramakrishnam Raju, M. V.; Chen, Y.; Nantz, M. H.; Conklin, D. J.; Fu, X. A. Aldehyde detection in electronic cigarette aerosols. ACS Omega 2017, 2, 1207– 1214,  DOI: 10.1021/acsomega.6b00489

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    Aldehyde Detection in Electronic Cigarette Aerosols

    Ogunwale, Mumiye A.; Li, Mingxiao; Ramakrishnam Raju, Mandapati V.; Chen, Yizheng; Nantz, Michael H.; Conklin, Daniel J.; Fu, Xiao-An

    ACS Omega (2017), 2 (3), 1207-1214CODEN: ACSODF; ISSN:2470-1343. (American Chemical Society)

    Acetaldehyde, acrolein, and formaldehyde are principal toxic aldehydes present in cigarette smoke that contribute to the risk of cardiovascular disease and non-cancerous pulmonary disease. The rapid growth of use of electronic cigarettes (e-cigarette) has raised concerns over emissions of these harmful aldehydes. This work dets. emissions of these aldehydes in both free and bound (aldehydehemiacetal) forms as well as other carbonyls from the use of e-cigarettes. A novel silicon microreactor with a coating phase of 4-(2-aminooxyethyl)-morpholin-4-ium chloride (AMAH) was used to trap carbonyl compds. in the aerosols of e-cigarettes via oximation reactions. AMAH-aldehyde adducts were measured by gas chromatog.-mass spectrometry (GC-MS). 1H NMR spectroscopy was used to analyze hemiacetals in the aerosols. These aldehydes were detected in the aerosols of all e-cigarettes. Newer generation e-cigarette devices generated more aldehydes than the first-generation e-cigarettes because of higher battery power output. Formaldehydehemiacetal was detected in the aerosols generated from some e-liqs. using the newer e-cigarette device at a battery power output of 11.7 W and above. The emission of these aldehydes from all ecigarettes, esp. higher levels of aldehydes from the newer generation e-cigarette devices indicates the risk of use of e-cigarettes.

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17. 17

    Conklin, D. J.; Ogunwale, M. A.; Chen, Y.; Theis, W. S.; Nantz, M. H.; Fu, X. A.; Chen, L. C.; Riggs, D. W.; Lorkiewicz, P.; Bhatnagar, A.; Srivastava, S. Electronic cigarette-generated aldehydes: The contribution of e-liquid components to their formation and the use of urinary aldehyde metabolites as biomarkers of exposure. Aerosol Sci. Technol. 2018, 52, 1219– 1232,  DOI: 10.1080/02786826.2018.1500013

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    Electronic cigarette-generated aldehydes: The contribution of e-liquid components to their formation and the use of urinary aldehyde metabolites as biomarkers of exposure

    Conklin, Daniel J.; Ogunwale, Mumiye A.; Chen, Yizheng; Theis, Whitney S.; Nantz, Michael H.; Fu, Xiao-An; Chen, Lung-Chi; Riggs, Daniel W.; Lorkiewicz, Pawel; Bhatnagar, Aruni; Srivastava, Sanjay

    Aerosol Science and Technology (2018), 52 (11), 1219-1232CODEN: ASTYDQ; ISSN:0278-6826. (Taylor & Francis, Inc.)

    Electronic cigarettes (e-cigarette) have emerged as a popular electronic nicotine delivery system (ENDS) in the last decade. Despite the absence of combustion products and toxins such as carbon monoxide (CO) and tobacco-specific nitrosamines (TSNA), carbonyls including short-chain, toxic aldehydes have been detected in e-cigarette-derived aerosols up to levels found in tobacco smoke. Given the health concerns regarding exposures to toxic aldehydes, understanding both aldehyde generation in e-cigarette and e-cigarette exposure is crit. Thus, we measured aldehydes generated in aerosols derived from propylene glycol (PG): vegetable glycerin (VG) mixts. and from com. e-liqs. with flavorants using a state-of-the-art carbonyl trap and mass spectrometry. To track e-cigarette exposure in mice, we measured urinary metabolites of 4 aldehydes using ULPC-MS/MS or GC-MS. Aldehyde levels, regardless of abundance (satd.: formaldehyde, acetaldehyde » unsatd.: acrolein, crotonaldehyde), were dependent on the PG:VG ratio and the presence of flavorants. The metabolites of 3 aldehydes - formate, acetate, and 3-hydroxypropyl mercapturic acid (3-HPMA; acrolein metabolite) - were increased in urine after e-cigarette aerosol and mainstream cigarette smoke (MCS) exposures, but the crotonaldehyde metabolite (3-hydroxy-1-methylpropylmercapturic acid, HPMMA) was increased only after MCS exposure. Interestingly, exposure to menthol-flavored e-cigarette aerosol increased the levels of urinary 3-HPMA and sum of nicotine exposure (nicotine, cotinine, trans-3'-hydroxycotinine) relative to exposure to a Classic Tobacco-flavored e-cigarette aerosol. Comparing these findings with aerosols of other ENDS and by measuring aldehyde-derived metabolites in human urine following exposure to e-cigarette aerosols will further our understanding of the relationship between ENDS use, aldehyde exposure, and health risk.

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    Li, Y.; Burns, A. E.; Tran, L. N.; Abellar, K. A.; Poindexter, M.; Li, X.; Madl, A. K.; Pinkerton, K. E.; Nguyen, T. B. Impact of e-liquid composition, coil temperature, and puff topography on the aerosol chemistry of electronic cigarettes. Chem. Res. Toxicol. 2021, 34, 1640– 1654,  DOI: 10.1021/acs.chemrestox.1c00070

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    18

    Impact of e-Liquid Composition, Coil Temperature, and Puff Topography on the Aerosol Chemistry of Electronic Cigarettes

    Li, Yichen; Burns, Amanda E.; Tran, Lillian N.; Abellar, Karizza A.; Poindexter, Morgan; Li, Xiaohan; Madl, Amy K.; Pinkerton, Kent E.; Nguyen, Tran B.

    Chemical Research in Toxicology (2021), 34 (6), 1640-1654CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)

    E-cigarette aerosol is a complex mixt. of gases and particles with a compn. that is dependent on the e-liq. formulation, puffing regimen, and device operational parameters. This work investigated mainstream aerosols from a third generation device, as a function of coil temp. (315-510°F, or 157-266°C), puff duration (2-4 s), and the ratio of propylene glycol (PG) to vegetable glycerin (VG) in e-liq. (100:0-0:100). Targeted and untargeted analyses using liq. chromatog. high-resoln. mass spectrometry, gas chromatog., in situ chem. ionization mass spectrometry, and gravimetry were used for chem. characterizations. PG and VG were found to be the major constituents (>99%) in both phases of the aerosol. Most e-cigarette components were obsd. to be volatile or semivolatile under the conditions tested. PG was found almost entirely in the gas phase, while VG had a sizable particle component. Nicotine was only obsd. in the particle phase. The prodn. of aerosol mass and carbonyl degrdn. products dramatically increased with higher coil temp. and puff duration, but decreased with increasing VG fraction in the e-liq. An exception is acrolein, which increased with increasing VG. The formation of carbonyls was dominated by the heat-induced dehydration mechanism in the temp. range studied, yet radical reactions also played an important role. The findings from this study identified open questions regarding both pathways. The vaping process consumed PG significantly faster than VG under all tested conditions, suggesting that e-liqs. become more enriched in VG and the exposure to acrolein significantly increases as vaping continues. It can be estd. that a 30:70 initial ratio of PG:VG in the e-liq. becomes almost entirely VG when 60-70% of e-liq. remains during the vaping process at 375°F (191°C). This work underscores the need for further research on the puffing lifecycle of e-cigarettes.

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19. 19

    Vreeke, S.; Korzun, T.; Luo, W.; Jensen, R. P.; Peyton, D. H.; Strongin, R. M. Dihydroxyacetone levels in electronic cigarettes: Wick temperature and toxin formation. Aerosol Sci. Technol. 2018, 52, 370– 376,  DOI: 10.1080/02786826.2018.1424316

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    19

    Dihydroxyacetone levels in electronic cigarettes: Wick temperature and toxin formation

    Vreeke, Shawna; Korzun, Tetiana; Luo, Wentai; Jensen, R. Paul; Peyton, David H.; Strongin, Robert M.

    Aerosol Science and Technology (2018), 52 (4), 370-376CODEN: ASTYDQ; ISSN:0278-6826. (Taylor & Francis, Inc.)

    Recently, we reported the presence of dihydroxyacetone (DHA), the active ingredient in sunless tanners, in the aerosol of an electronic cigarette. DHA has been shown to react with DNA in vitro. The FDA restricts the use of DHA to external application only. It states that it should not be inhaled, ingested, or come into contact with any areas contg. mucous membranes, due to unknown risk. Herein, the quantification of DHA in the aerosols of three brands of e-cigarettes has been carried out. These included two devices with horizontal heating coil configurations as well as one with a sub-ohm resistance vertical heating coil. In order to understand and begin to address the origin of DHA and related aerosol products, the wicking properties of the three e-cigarettes were compared. DHA levels were analyzed by a combination of GS/MS and 1H NMR. DHA was found in all three e-cigarettes, with substantially less in the sub-ohm, vertical coil device as compared to the horizontal coil devices (e.g., 0.088μg/puff vs. 2.29μg/puff, resp.). Correspondingly, the temp. of the wet layer of the wick for the vertical coil was relatively stable, compared to the wicks for the horizontal coils, upon increasing battery power output. The temp. measurements reported are a simple means for comparing devices with different design properties during operation. 2018 American Assocn. for Aerosol Research.

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20. 20

    Landmesser, A.; Scherer, G.; Pluym, N.; Niessner, R.; Scherer, M. A novel quantification method for sulfur-containing biomarkers of formaldehyde and acetaldehyde exposure in human urine and plasma samples. Anal. Bioanal. Chem. 2020, 412, 7535– 7546,  DOI: 10.1007/s00216-020-02888-y

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    20

    A novel quantification method for sulfur-containing biomarkers of formaldehyde and acetaldehyde exposure in human urine and plasma samples

    Landmesser, Anne; Scherer, Gerhard; Pluym, Nikola; Niessner, Reinhard; Scherer, Max

    Analytical and Bioanalytical Chemistry (2020), 412 (27), 7535-7546CODEN: ABCNBP; ISSN:1618-2642. (Springer)

    A novel method for the quantification of the sulfur-contg. metabolites of formaldehyde (thiazolidine carboxylic acid (TCA) and thiazolidine carbonyl glycine (TCG)) and acetaldehyde (Me thiazolidine carboxylic acid (MTCA) and Me thiazolidine carbonyl glycine (MTCG)) was developed and validated for human urine and plasma samples. Targeting the sulfur-contg. metabolites of formaldehyde and acetaldehyde in contrast to the commonly used biomarkers formate and acetate overcomes the high intra- and inter-individual variance. Due to their involvement in various endogenous processes, formate and acetate lack the required specificity for assessing the exposure to formaldehyde and acetaldehyde, resp. Validation was successfully performed according to FDA's Guideline for Bioanal. Method Validation (2018), showing excellent performance with regard to accuracy, precision, and limits of quantification (LLOQ). TCA, TCG, and MTCG proved to be stable under all studied conditions, whereas MTCA showed a depletion after 21 mo. The method was applied to a set of pilot samples derived from smokers who consumed unfiltered cigarettes spiked with 13C-labeled propylene glycol and 13C-labeled glycerol. These compds. were used as potential precursors for the formation of 13C-formaldehyde and 13C-acetaldehyde during combustion. Plasma concns. were significantly lower as compared to urine, suggesting urine as suitable matrix for a biomonitoring. A smoking-related increase of unlabeled biomarker concns. could not be shown due to the ubiquitous distribution in the environment. While the metabolites of 13C-acetaldehyde were not detected, the described method allowed for the quantification of 13C-formaldehyde uptake from cigarette smoking by targeting the biomarkers 13C-TCA and 13C-TCG in urine.

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21. 21

    Redtenbacher, J. (1870) Annalen der Chemie und Pharmacie: Supplementband. C.F. Winter.

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22. 22

    Laino, T.; Tuma, C.; Curioni, A.; Jochnowitz, E.; Stolz, S. A revisited picture of the mechanism of glycerol dehydration. J. Phys. Chem. A 2011, 115, 3592– 3595,  DOI: 10.1021/jp201078e

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    22

    A Revisited Picture of the Mechanism of Glycerol Dehydration

    Laino, Teodoro; Tuma, Christian; Curioni, Alessandro; Jochnowitz, Evan; Stolz, Steffen

    Journal of Physical Chemistry A (2011), 115 (15), 3592-3595CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)

    The dehydration mechanism of neutral glycerol in the gas phase was investigated by means of metadynamics simulations. Structures, vibrational frequencies, Gibbs free energy barriers, and rate consts. at 800 K were computed for the different steps involved in the pyrolytic process. In this article, we provide a novel mechanism for the dehydration of neutral glycerol, proceeding via formation of glycidol with a barrier of 66.8 kcal/mol. The formation of glycidol is the rate limiting step of the overall decompn. process. Once formed, glycidol converts into 3-hydroxypropanal with a barrier of 49.5 kcal/mol. 3-Hydroxypropanal can decomp. further into acrolein or into formaldehyde and vinyl-alc. with barriers of 53.9 and 35.3 kcal/mol, resp. These findings offer new insights to available exptl. data based on glycerol pyrolysis studies performed with isotopic labeling and on the interpretation of the chem. of glycerol and sugars in pyrolytic conditions.

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23. 23

    Paine, T. K.; England, J.; Que, L., Jr. Iron-catalyzed C2-C3 bond cleavage of phenylpyruvate with O2: insight into aliphatic C-C bond-cleaving dioxygenases. Chemistry 2007, 13, 6073– 6081,  DOI: 10.1002/chem.200601844

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    23

    Iron-catalyzed C2-C3 bond cleavage of phenylpyruvate with O2: insight into aliphatic C-C bond-cleaving dioxygenases

    Paine, Tapan Kanti; England, Jason; Que, Lawrence, Jr.

    Chemistry - A European Journal (2007), 13 (21), 6073-6081, S6073/1-S6073/10CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Fe(II)-phenylpyruvate complexes of tetradentate tris(6-methyl-2-pyridylmethyl)amine (6-Me3-TPA) and tridentate benzyl bis(2-quinolinylmethyl)amine (Bn-BQA) were prepd. to gain insight into C-C bond cleavage catalyzed by dioxygenase enzymes. The complexes the authors prepd. and characterized are [Fe(6-Me3-tpa)(prv)][BPh4] (1), [Fe2(6-Me3-tpa)2(pp)][(BPh4)2] (2), and [Fe2(6-Me3-tpa)2(2'-NO2-pp)][(BPh4)2] (3), [Fe(6-Me3-tpa)(pp-Me)][BPh4] (4), [Fe(6-Me3-tpa)(CN-pp-Et)][BPh4] (5), and [Fe(Bn-bqa)(pp)] (8), in which PRV is pyruvate, PP is the enolate form of phenylpyruvate, 2'-NO2-PP is the enolate form of 2'-nitrophenylpyruvate, PP-Me is the enolate form of Me phenylpyruvate, and CN-PP-Et is the enolate form of Et-3-cyanophenylpyruvate. The structures of mononuclear complexes 1 and 5 were detd. by single-crystal x-ray diffraction. Both the PRV ligand in 1 and the CN-PP-Et ligand in 5 bind to the Fe(II) center in a bidentate manner and form 5-membered chelate rings, but the α-keto moiety is in the enolate form in 5 with concomitant loss of a C-Hβ proton. The PP ligands of 2, 3, 4, and 8 react with dioxygen to form benzaldehyde and oxalate products, which indicates that the C2-C3 PP bond is cleaved, in contrast to cleavage of the C1-C2 bond previously obsd. for complexes that do not contain α-keto-carboxylate ligands in the enolate form. These reactions serve as models for metal-contg. dioxygenase enzymes that catalyze the cleavage of aliph. C-C bonds.

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24. 24

    Corma, A.; Huber, G. W.; Sauvanaud, L.; O’Connor, P. Biomass to chemicals: catalytic conversion of glycerol/water mixtures into acrolein, reaction network. J. Catal. 2008, 257, 163– 171,  DOI: 10.1016/j.jcat.2008.04.016

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    24

    Biomass to chemicals: Catalytic conversion of glycerol/water mixtures into acrolein, reaction network

    Corma, Avelino; Huber, George W.; Sauvanaud, Laurent; O'Connor, Paul

    Journal of Catalysis (2008), 257 (1), 163-171CODEN: JCTLA5; ISSN:0021-9517. (Elsevier)

    Acrolein was obtained by reaction of gas-phase glycerol/water mixts. in presence of USY zeolite, Y-zeolite catalysts in a silica/alumina matrix, and ZSM-5 zeolite mixed with a clay binder. The glycerol is a byproduct from biodiesel prodn. from biomass. Glycerol was converted through a series of reactions involving dehydration, cracking, and hydrogen transfer and catalyzed by the acid sites of the zeolite. Acrolein was the major product; short olefins, aroms., acetaldehyde, hydroxyacetone, acids, and acetone also were formed through a complex reaction network.

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25. 25

    Jensen, R. P.; Strongin, R. M.; Peyton, D. H. Solvent chemistry in the electronic cigarette reaction vessel. Sci. Rep. 2017, 7, 42549,  DOI: 10.1038/srep42549

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    25

    Solvent Chemistry in the Electronic Cigarette Reaction Vessel

    Jensen, R. Paul; Strongin, Robert M.; Peyton, David H.

    Scientific Reports (2017), 7 (), 42549CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)

    Knowledge of the mechanism of formation, levels and toxicol. profiles of the chem. products in the aerosols (i.e., vapor plus particulate phases) of e-cigarettes is needed in order to better inform basic research as well as the general public, regulators, and industry. To date, studies of e-cigarette emissions have mainly focused on chromatog. techniques for quantifying and comparing the levels of selected e-cigarette aerosol components to those found in traditional cigarettes. E-cigarettes heat and aerosolize the solvents propylene glycol (PG) and glycerol (GLY), thereby affording unique product profiles as compared to traditional cigarettes. The chem. literature strongly suggests that there should be more compds. produced by PG and GLY than have been reported in e-cigarette aerosols to date. Herein we report an extensive investigation of the products derived from vaporizing PG and GLY under mild, single puff conditions. This has led to the discovery of several new compds. produced under vaping conditions. Prior reports on e-cigarette toxin prodn. have emphasized temp. as the primary variable in solvent degrdn. In the current study, the mol. pathways leading to enhanced PG/GLY reactivity are described, along with the most impactful chem. conditions promoting byproduct prodn.

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26. 26

    Samburova, V.; Bhattarai, C.; Strickland, M.; Darrow, L.; Angermann, J.; Son, Y.; Khlystov, A. Aldehydes in exhaled breath during e-cigarette vaping: Pilot study results. Toxics 2018, 6, 46,  DOI: 10.3390/toxics6030046

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    26

    Aldehydes in exhaled breath during E-cigarette vaping: pilot study results

    Samburova, Vera; Bhattarai, Chiranjivi; Strickland, Matthew; Darrow, Lyndsey; Angermann, Jeff; Son, Yeongkwon; Khlystov, Andrey

    Toxics (2018), 6 (3), 46CODEN: TOXIC8; ISSN:2305-6304. (MDPI AG)

    Several studies have shown the presence of aldehydes (i.e., formaldehyde, acrolein) in mainstream emissions of some e-cigarettes. For this reason, concerns have been raised regarding potential toxicity. The purpose of this research was to measure levels of carbonyls in exhaled breath of e-cigarette users during "vaping" sessions and est. the respiratory tract (RT) uptake of specific aldehydes, including formaldehyde and acetaldehyde. We measured concns. of 12 carbonyls in e-cigarette aerosols produced directly by e-cigarettes and in the exhaled breath of 12 participants (19 sessions). Carbonyls were sampled on 2,4-dinitrophenylhydrazine (DNPH) cartridges and analyzed with high performance liq. chromatog. (HPLC) coupled with a UV/Vis photodiode detector. We found that in most cases, levels of aldehydes and Me Et ketone (MEK) were significantly higher (2-125 times) in exhaled e-cigarette breaths than in pre-exposed breath. Exposure levels for the most abundant individual carbonyls in e-cigarette emissions-formaldehyde, acetaldehyde, acrolein-were between the limit of quantification (LOQ) and 24.4 μg•puff-1. The mean retention of formaldehyde in the respiratory tract was 99.7 ± 0.9% for all participants, while acetaldehyde retention was 91.6 ± 9.9%. Within the limitation of a small no. of participants, our results showed that there is an increase in breath carbonyls during e-cigarette use.

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27. 27

    McRobbie, H.; Bullen, C.; Hartmann-Boyce, J.; Hajek, P. Electronic cigarettes for smoking cessation and reduction. Cochrane Database Syst. Rev. 2014, CD010216,  DOI: 10.1002/14651858.CD010216.pub2

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28. 28

    Hecht, S. S.; Carmella, S. G.; Kotandeniya, D.; Pillsbury, M. E.; Chen, M.; Ransom, B. W.; Vogel, R. I.; Thompson, E.; Murphy, S. E.; Hatsukami, D. K. Evaluation of toxicant and carcinogen metabolites in the urine of e-cigarette users versus cigarette smokers. Nicotine Tob. Res. 2015, 17, 704– 709,  DOI: 10.1093/ntr/ntu218

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    Evaluation of toxicant and carcinogen metabolites in the urine of e-cigarette users versus cigarette smokers

    Hecht, Stephen S.; Carmella, Steven G.; Kotandeniya, Delshanee; Pillsbury, Makenzie E.; Chen, Menglan; Ransom, Benjamin W. S.; Vogel, Rachel Isaksson; Thompson, Elizabeth; Murphy, Sharon E.; Hatsukami, Dorothy K.

    Nicotine & Tobacco Research (2015), 17 (6), 704-709CODEN: NTREF6; ISSN:1462-2203. (Oxford University Press)

    Introduction: Electronic cigarettes (e-cigarettes) are rapidly increasing in popularity but little information is available on their potential toxic or carcinogenic effects. Methods: Twenty-eight e-cigarette smokers who had not smoked tobacco cigarettes for at least 2 mo provided urine samples which were analyzed by validated methods for a suite of toxicant and carcinogen metabolites including 1-hydroxypyrene (1-HOP), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), 3-hydroxypropylmercapturic acid (3-HPMA), 2-hydroxypropylmercapturic acid (2-HPMA), 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), S-phenylmercapturic acid (SPMA), nicotine, and cotinine. Levels of these compds. were compared to those found in cigarette smokers from three previous studies. Results: Levels of 1-HOP, total NNAL, 3-HPMA, 2-HPMA, HMPMA, and SPMA were significantly lower in the urine of e-cigarette users compared to cigarette smokers. Levels of nicotine and cotinine were significantly lower in e-cigarette users compared to cigarette smokers in one study but not in another. Conclusions: With respect to the compds. analyzed here, e-cigarettes have a more favorable toxicity profile than tobacco cigarettes.

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29. 29

    Lorkiewicz, P.; Riggs, D. W.; Keith, R. J.; Conklin, D. J.; Xie, Z.; Sutaria, S.; Lynch, B.; Srivastava, S.; Bhatnagar, A. Comparison of urinary biomarkers of exposure in humans using electronic cigarettes, combustible cigarettes, and smokeless tobacco. Nicotine Tob. Res. 2019, 21, 1228– 1238,  DOI: 10.1093/ntr/nty089

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    29

    Comparison of urinary biomarkers of exposure in humans using electronic cigarettes, combustible cigarettes, and smokeless tobacco

    Lorkiewicz, Pawel; Rigg, Daniel W.; Keith, Rachel J.; Conklin, Daniel J.; Xie, Zhengzhi; Sutari, Saurin; Lync, Blake; Srivastava, Sanjay; Bhatnagar, Aruni

    Nicotine & Tobacco Research (2019), 21 (9), 1228-1238CODEN: NTREF6; ISSN:1469-994X. (Oxford University Press)

    Background: Cigarette smoking is assocd. with an increase in cardiovascular disease risk, attributable in part to reactive volatile org. chems. (VOCs). However, little is known about the extent of VOC exposure due to the use of other tobacco products. Methods: We recruited 48 healthy, tobacco users in four groups: cigarette, smokeless tobacco, occasional users of first generation e-cigarette and e-cigarette menthol and 12 healthy nontobacco users. After abstaining for 48 h, tobacco users used an assigned product. Urine was collected at baseline followed by five collections over a 3-h period to measure urinary metabolites of VOCs, nicotine, and tobacco alkaloids. Results: Urinary levels of nicotine were ≃2-fold lower in occasional e-cigarette and smokeless tobacco users than in the cigarette smokers; cotinine and 3-hydroxycotinine levels were similar in all groups. Compared with nontobacco users, e-cigarette users had higher levels of urinary metabolites of xylene, cyanide, styrene, ethylbenzene, and benzene at baseline and elevated urinary levels of metabolites of xylene, N,N-dimethylformamide, and acrylonitrile after e-cigarette use. Metabolites of acrolein, crotonaldehyde, and 1,3-butadiene were significantly higher in smokers than in users of other products or nontobacco users. VOC metabolite levels in smokeless tobacco group were comparable to those found in nonusers with the exception of xylene metabolite- 2-methylhippuric acid (2MHA), which was almost three fold higher than in nontobacco users. Conclusions: Smoking results in exposure to a range of VOCs at concns. higher than those obsd. with other products, and first generation e-cigarette use is assocd. with elevated levels of N,N-dimethylformamide and xylene metabolites. Implications: This study shows that occasional users of first generation e-cigarettes have lower levels of nicotine exposure than the users of combustible cigarettes. Compared with combustible cigarettes, e-cigarettes, and smokeless tobacco products deliver lower levels of most VOCs, with the exception of xylene, N,N-dimethylformamide, and acrylonitrile, whose metabolite levels were higher in the urine of e-cigarette users than nontobacco users. Absence of anatabine in the urine of e-cigarette users suggests that measuring urinary levels of this alkaloid may be useful in distinguishing between users of e-cigarettes and combustible cigarettes. However, these results have to be validated in a larger cohortcomprised of users of e-cigarettes of multiple brands.

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30. 30

    De Jesús, V. R.; Bhandari, D.; Zhang, L.; Reese, C.; Capella, K.; Tevis, D.; Zhu, W.; Del Valle-Pinero, A. Y.; Lagaud, G.; Chang, J. T.; van Bemmel, D.; Kimmel, H. L.; Sharma, E.; Goniewicz, M. L.; Hyland, A.; Blount, B. C. Urinary biomarkers of exposure to volatile organic compounds from the Population Assessment of Tobacco and Health Study Wave 1 (2013-2014). Int. J. Environ. Res. Public Health 2020, 17, 5408,  DOI: 10.3390/ijerph17155408

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    30

    Urinary biomarkers of exposure to volatile organic compounds from the population assessment of tobacco and health study wave 1 (2013-2014)

    De Jesus, Victor R.; Bhandari, Deepak; Zhang, Luyu; Reese, Christopher; Capella, Kimberly; Tevis, Denise; Zhu, Wanzhe; Del Valle-Pinero, Arseima Y.; Lagaud, Guy; Chang, Joanne T.; van Bemmel, Dana; Kimmel, Heather L.; Sharma, Eva; Goniewicz, Maciej L.; Hyland, Andrew; Blount, Benjamin C.

    International Journal of Environmental Research and Public Health (2020), 17 (15), 5408CODEN: IJERGQ; ISSN:1660-4601. (MDPI AG)

    Volatile org. compds. (VOCs) are ubiquitous in the environment. In the United States (U.S.), tobacco smoke is the major non-occupational source of exposure to many harmful VOCs. Exposure to VOCs can be assessed by measuring their urinary metabolites (VOCMs). The Population Assessment of Tobacco and Health (PATH) Study is a U.S. national longitudinal study of tobacco use in the adult and youth civilian non-institutionalized population. We measured 20 VOCMs in urine specimens from a subsample of adults in Wave 1 (W1) (2013-2014) to characterize VOC exposures among tobacco product users and non-users. We calcd. weighted geometric means (GMs) and percentiles of each VOCM for exclusive combustible product users (smokers), exclusive electronic cigarette (e-cigarette) users, exclusive smokeless product users, and tobacco product never users. We produced linear regression models for six VOCMs with sex, age, race, and tobacco user group as predictor variables. Creatinine-ratioed levels of VOCMs from exposure to acrolein, crotonaldehyde, isoprene, acrylonitrile, and 1,3-butadiene were significantly higher in smokers than in never users. Small differences of VOCM levels among exclusive e-cigarette users and smokeless users were obsd. when compared to never users. Smokers showed higher VOCM concns. than e-cigarette, smokeless, and never users. Urinary VOC metabolites are useful biomarkers of exposure to harmful VOCs.

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31. 31

    Hazen, S. L.; d’Avignon, A.; Anderson, M. M.; Hsu, F. F.; Heinecke, J. W. Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to oxidize alpha-amino acids to a family of reactive aldehydes. Mechanistic studies identifying labile intermediates along the reaction pathway. J. Biol. Chem. 1998, 273, 4997– 5005,  DOI: 10.1074/jbc.273.9.4997

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    31

    Human neutrophils employ the myeloperoxidase-hydrogen peroxide-chloride system to oxidize α-amino acids to a family of reactive aldehydes. Mechanistic studies identifying labile intermediates along the reaction pathway

    Hazen, Stanley L.; D'avignon, Andre; Anderson, Melissa M.; Hsu, Fong F.; Heinecke, Jay W.

    Journal of Biological Chemistry (1998), 273 (9), 4997-5005CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)

    We have recently demonstrated that neutrophils oxidize nearly all of the amino acids commonly found in plasma to a corresponding family of aldehydes in high yield. The reaction is mediated by hypochlorous acid (HOCI), the major oxidant generated by the myeloperoxidase-H2O2-Cl- system of phagocytes. We now present evidence for the underlying mechanism of this reaction, including the structural requirements and reaction intermediates formed. Utilizing mass spectrometry and isotopically labeled amino acids, we rule out hydrogen atom abstraction from the α-carbon as the initial event in aldehyde formation during amino acid oxidn., a pathway known to occur with ionizing radiation. Aldehyde generation from amino acids required the presence of an α-amino moiety; β- and ε-amino acids did not form aldehydes upon oxidn. by either the myeloperoxidase system or HOCl, generating stable monochloramines instead. UV difference spectroscopy, high pressure liq. chromatog., and multinuclear (1H,16N) NMR spectroscopy established that the conversion of α-amino acids into aldehydes begins with generation of an unstable α-monochloramine, which subsequently decomps. to yield an aldehyde. Precursor product relationships between α-amino acid and α-monochloramine, and α-monochloramine and aldehyde were confirmed by high pressure liq. chromatog. purifn. of the reaction intermediate and subsequent 1H and S1N NMR spectroscopy. Collectively, these results detail the chem. mechanism and reaction intermediates generated during conversion of amino acids into aldehydes by myeloperoxidase-generated HOCl.

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32. 32

    Stevens, J. F.; Maier, C. S. Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. Mol. Nutr. Food Res. 2008, 52, 7– 25,  DOI: 10.1002/mnfr.200700412

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    Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease

    Stevens, Jan F.; Maier, Claudia S.

    Molecular Nutrition & Food Research (2008), 52 (1), 7-25CODEN: MNFRCV; ISSN:1613-4125. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chem. reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidn. of polyunsatd. fatty acids, and Strecker degrdn. of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degrdn. of threonine and amine oxidase-mediated degrdn. of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biol. relevance of this reaction is not clear. The biol. effects of acrolein are a consequence of its reactivity towards biol. nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in crit. regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromols. which may result in mutations, altered gene transcription, and modulation of apoptosis.

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    Conklin, D. J.; Haberzettl, P.; Lee, J.; Srivastava, S. (2011) Aldehydes and Cardiovascular Disease., In Environmental Cardiology: Pollution and Heart Disease (Bhatnagar, A., Ed.) p 390, Royal Society of Chemistry, London, England.

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34. 34

    Tevis, D. S.; Flores, S. R.; Kenwood, B. M.; Bhandari, D.; Jacob, P., 3rd; Liu, J.; Lorkiewicz, P. K.; Conklin, D. J.; Hecht, S. S.; Goniewicz, M. L.; Blount, B. C.; De Jesus, V. R. Harmonization of acronyms for volatile organic compound metabolites using a standardized naming system. Int. J. Hyg. Environ. Health 2021, 235, 113749,  DOI: 10.1016/j.ijheh.2021.113749

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    Harmonization of acronyms for volatile organic compound metabolites using a standardized naming system

    Tevis, Denise S.; Flores, Sharon R.; Kenwood, Brandon M.; Bhandari, Deepak; Jacob, Peyton 3rd; Liu, Jia; Lorkiewicz, Pawel K.; Conklin, Daniel J.; Hecht, Stephen S.; Goniewicz, Maciej L.; Blount, Benjamin C.; De Jesus, Victor R.

    International Journal of Hygiene and Environmental Health (2021), 235 (), 113749CODEN: IJEHFT; ISSN:1438-4639. (Elsevier GmbH)

    Increased interest in volatile org. compd. (VOC) exposure has led to an increased need for consistent, systematic, and informative naming of VOC metabolites. As anal. methods have expanded to include many metabolites in a single assay, the no. of acronyms in use for a single metabolite has expanded in an unplanned and inconsistent manner due to a lack of guidance or group consensus. Even though the measurement of VOC metabolites is a well-established means to investigate exposure to VOCs, a formal attempt to harmonize acronyms amongst investigators has not been published. The aim of this work is to establish a system of acronym naming that provides consistency in current acronym usage and a foundation for creating acronyms for future VOC metabolites.

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35. 35

    Jin, L.; Lynch, J.; Richardson, A.; Lorkiewicz, P.; Srivastava, S.; Theis, W.; Shirk, G.; Hand, A.; Bhatnagar, A.; Srivastava, S.; Conklin, D. J. Electronic cigarette solvents, pulmonary irritation, and endothelial dysfunction: role of acetaldehyde and formaldehyde. Am. J. Physiol. Heart Circ. Physiol. 2021, 320, H1510– H1525,  DOI: 10.1152/ajpheart.00878.2020

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    There is no corresponding record for this reference.
36. 36

    Conklin, D. J.; Malovichko, M. V.; Zeller, I.; Das, T. P.; Krivokhizhina, T. V.; Lynch, B. H.; Lorkiewicz, P.; Agarwal, A.; Wickramasinghe, N.; Haberzettl, P.; Sithu, S. D.; Shah, J.; O’Toole, T. E.; Rai, S. N.; Bhatnagar, A.; Srivastava, S. Biomarkers of chronic acrolein inhalation exposure in mice: Implications for tobacco product-induced toxicity. Toxicol. Sci. 2017, 158, 263– 274,  DOI: 10.1093/toxsci/kfx095

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    Biomarkers of chronic acrolein inhalation exposure in mice: implications for tobacco product-induced toxicity

    Conklin, Daniel J.; Malovichko, Marina V.; Zeller, Iris; Das, Trinath P.; Krivokhizhina, Tatiana V.; Lynch, Blake H.; Lorkiewicz, Pawel; Agarwal, Abhinav; Wickramasinghe, Nalinie; Haberzettl, Petra; Sithu, Srinivas D.; Shah, Jasmit; O'Toole, Timothy E.; Rai, Shesh N.; Bhatnagar, Aruni; Srivastava, Sanjay

    Toxicological Sciences (2017), 158 (2), 263-274CODEN: TOSCF2; ISSN:1096-0929. (Oxford University Press)

    Exposure to tobacco smoke, which contains several harmful and potentially harmful constituents such as acrolein increases cardiovascular disease (CVD) risk. Although high acrolein levels induce pervasive cardiovascular injury, the effects of low-level exposure remain unknown and sensitive biomarkers of acrolein toxicity have not been identified. Identification of such biomarkers is essential to assess the toxicity of acrolein present at low levels in the ambient air or in new tobacco products such as e-cigarettes. Hence, we examd. the systemic effects of chronic (12 wk) acrolein exposure at concns. similar to those found in tobacco smoke (0.5 or 1 ppm). Acrolein exposure in mice led to a 2- to 3-fold increase in its urinary metabolite 3-hydroxypropyl mercapturic acid (3-HPMA) with an attendant increase in pulmonary levels of the acrolein-metabolizing enzymes, glutathione S-transferase P and aldose reductase, as well as several Nrf2-regulated antioxidant proteins. Markers of pulmonary endoplasmic reticulum stress and inflammation were unchanged. Exposure to acrolein suppressed circulating levels of endothelial progenitor cells (EPCs) and specific leukocyte subsets (eg, GR-1+ cells, CD19+ B-cells, CD4+ T-cells; CD11b+ monocytes) while other subsets (eg, CD8+ cells, NK1.1+ cells, Ly6C+ monocytes) were unchanged. Chronic acrolein exposure did not affect systemic glucose tolerance, platelet-leukocyte aggregates or microparticles in blood. These findings suggest that circulating levels of EPCs and specific leukocyte populations are sensitive biomarkers of inhaled acrolein injury and that low-level (<0.5 ppm) acrolein exposure (eg, in secondhand smoke, vehicle exhaust, e-cigarettes) could increase CVD risk by diminishing endothelium repair or by suppressing immune cells or both.

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37. 37

    Lorkiewicz, P. K.; Gibb, A. A.; Rood, B. R.; He, L.; Zheng, Y.; Clem, B. F.; Zhang, X.; Hill, B. G. Integration of flux measurements and pharmacological controls to optimize stable isotope-resolved metabolomics workflows and interpretation. Sci. Rep. 2019, 9, 13705,  DOI: 10.1038/s41598-019-50183-3

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    Integration of flux measurements and pharmacological controls to optimize stable isotope-resolved metabolomics workflows and interpretation

    Lorkiewicz Pawel K; Gibb Andrew A; Rood Benjamin R; Zheng Yuting; Hill Bradford G; Lorkiewicz Pawel K; He Liqing; Zhang Xiang; Gibb Andrew A; Clem Brian F

    Scientific reports (2019), 9 (1), 13705 ISSN:.

    Stable isotope-resolved metabolomics (SIRM) provides information regarding the relative activity of numerous metabolic pathways and the contribution of nutrients to specific metabolite pools; however, SIRM experiments can be difficult to execute, and data interpretation is challenging. Furthermore, standardization of analytical procedures and workflows remain significant obstacles for widespread reproducibility. Here, we demonstrate the workflow of a typical SIRM experiment and suggest experimental controls and measures of cross-validation that improve data interpretation. Inhibitors of glycolysis and oxidative phosphorylation as well as mitochondrial uncouplers serve as pharmacological controls, which help define metabolic flux configurations that occur under well-controlled metabolic states. We demonstrate how such controls and time course labeling experiments improve confidence in metabolite assignments as well as delineate metabolic pathway relationships. Moreover, we demonstrate how radiolabeled tracers and extracellular flux analyses integrate with SIRM to improve data interpretation. Collectively, these results show how integration of flux methodologies and use of pharmacological controls increase confidence in SIRM data and provide new biological insights.

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    Kage, S.; Kudo, K.; Ikeda, H.; Ikeda, N. Simultaneous determination of formate and acetate in whole blood and urine from humans using gas chromatography-mass spectrometry. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2004, 805, 113– 117,  DOI: 10.1016/j.jchromb.2004.02.029

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    38

    Simultaneous determination of formate and acetate in whole blood and urine from humans using gas chromatography-mass spectrometry

    Kage, Shigetoshi; Kudo, Keiko; Ikeda, Hideaki; Ikeda, Noriaki

    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2004), 805 (1), 113-117CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)

    We devised a sensitive and simple method for simultaneous detn. of formate and acetate in whole blood and urine from humans using gas chromatog.-mass spectrometry. Formate and acetate were alkylated with pentafluorobenzyl bromide in the mixt. of acetone and phosphate buffer (pH 6.8). The derivs. obtained were analyzed using gas chromatog.-mass spectrometry in pos.-ion electron ionization (EI) mode. The lower limit of detection for both compds. was 0.02 mM. The calibration curves for formate and acetate were linear over the concn. range from 0.05 to 5.0 mM. Accuracy and precision of the method were evaluated and the coeffs. of variation were within 10%. With use of this method, levels of formate and acetate in whole blood can be detd. in forensic cases.

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    Lamarre, S. G.; MacMillan, L.; Morrow, G. P.; Randell, E.; Pongnopparat, T.; Brosnan, M. E.; Brosnan, J. T. An isotope-dilution, GC-MS assay for formate and its application to human and animal metabolism. Amino Acids 2014, 46, 1885– 1891,  DOI: 10.1007/s00726-014-1738-7

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    An isotope-dilution, GC-MS assay for formate and its application to human and animal metabolism

    Lamarre, Simon G.; MacMillan, Luke; Morrow, Gregory P.; Randell, Edward; Pongnopparat, Theerawat; Brosnan, Margaret E.; Brosnan, John T.

    Amino Acids (2014), 46 (8), 1885-1891CODEN: AACIE6; ISSN:0939-4451. (Springer-Verlag GmbH)

    Formate, a crucial component of one-carbon metab., is increasingly recognized as an important intermediate in prodn. and transport of one-carbon units. Unlike tetrahydrofolate-linked intermediates, it is not restricted to the intracellular milieu so that circulating levels of formate can provide insight into cellular events. We report a novel isotope-diln., GC-MS assay employing derivatization by 2,3,4,5,6-pentafluorobenzyl bromide for the detn. of formate in biol. samples. This assay is robust and sensitive; it may be applied to the measurement of formate in serum, plasma and urine. We demonstrate how this method may be applied by providing the first characterization of formate levels in a human population; formate levels were higher in males than in females. We also show how this procedure may be applied for the measurement of in vivo kinetics of endogenous formate prodn. in exptl. animals.

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    Landmesser, A.; Scherer, M.; Scherer, G.; Sarkar, M.; Edmiston, J. S.; Niessner, R.; Pluym, N. Assessment of the potential vaping-related exposure to carbonyls and epoxides using stable isotope-labeled precursors in the e-liquid. Arch. Toxicol. 2021, 95, 2667– 2676,  DOI: 10.1007/s00204-021-03097-x

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    40

    Assessment of the potential vaping-related exposure to carbonyls and epoxides using stable isotope-labeled precursors in the e-liquid

    Landmesser, Anne; Scherer, Max; Scherer, Gerhard; Sarkar, Mohamadi; Edmiston, Jeffery S.; Niessner, Reinhard; Pluym, Nikola

    Archives of Toxicology (2021), 95 (8), 2667-2676CODEN: ARTODN; ISSN:0340-5761. (Springer)

    Abstr.: The formation of carbonyls and epoxides in e-cigarette (EC) aerosol is possible due to heating of the liq. constituents. However, high background levels of these compds. have inhibited a clear assessment of exposure during use of ECs. An EC contg. an e-liq. replaced with 10% of 13C-labeled propylene glycol and glycerol was used in a controlled use clin. study with 20 EC users. In addn., five smokers smoked cigarettes spiked with the described e-liq. Seven carbonyls (formaldehyde, acetaldehyde, acrolein, acetone, crotonaldehyde, methacrolein, propionaldehyde) were measured in the aerosol and the mainstream smoke. Corresponding biomarkers of exposure were detd. in the user's urine samples. 13C-labeled formaldehyde, acetaldehyde and acrolein were found in EC aerosol, while all seven labeled carbonyls were detected in smoke. The labeled biomarkers of exposure to formaldehyde (13C-thiazolidine carboxylic acid and 13C-N-(1,3-thiazolidine-4-carbonyl)glycine), acrolein (13C3-3-hydroxypropylmercapturic acid) and glycidol (13C3-dihydroxypropylmercapturic acid) were present in the urine of vapers indicating an EC use-specific exposure to these toxicants. However, other sources than vaping contribute to a much higher extent by several orders of magnitude to the overall exposure of these toxicants. Comparing data for the native (unlabeled) and the labeled (exposure-specific) biomarkers revealed vaping as a minor source of user's exposure to these toxicants while other carbonyls and epoxides were not detectable in the EC aerosol.

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41. 41

    DeJarnett, N.; Conklin, D. J.; Riggs, D. W.; Myers, J. A.; O’Toole, T. E.; Hamzeh, I.; Wagner, S.; Chugh, A.; Ramos, K. S.; Srivastava, S.; Higdon, D.; Tollerud, D. J.; DeFilippis, A.; Becher, C.; Wyatt, B.; McCracken, J.; Abplanalp, W.; Rai, S. N.; Ciszewski, T.; Xie, Z.; Yeager, R.; Prabhu, S. D.; Bhatnagar, A. Acrolein exposure is associated with increased cardiovascular disease risk. J. Am. Heart Assoc. 2014, 3, e000934  DOI: 10.1161/JAHA.114.000934

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    There is no corresponding record for this reference.
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    Kleinnijenhuis, A. J.; Staal, Y. C. M.; Duistermaat, E.; Engel, R.; Woutersen, R. A. The determination of exogenous formaldehyde in blood of rats during and after inhalation exposure. Food Chem. Toxicol. 2013, 52, 105– 112,  DOI: 10.1016/j.fct.2012.11.008

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    42

    The determination of exogenous formaldehyde in blood of rats during and after inhalation exposure

    Kleinnijenhuis, Anne J.; Staal, Yvonne C. M.; Duistermaat, Evert; Engel, Roel; Woutersen, Ruud A.

    Food and Chemical Toxicology (2013), 52 (), 105-112CODEN: FCTOD7; ISSN:0278-6915. (Elsevier Ltd.)

    Formaldehyde (FA) is suspected of being assocd. with the development of leukemia. An inhalation expt. with FA was performed in rats to study whether FA can enter the blood and could thus cause systemic toxicity in remote tissues such as the bone marrow. Therefore, a sophisticated anal. method was developed to detect blood concns. of FA during and after single 6-h exposure by inhalation. In order to differentiate between exogenous and endogenous FA the rats were exposed to stable isotope (13C) labeled FA by inhalation. During and after exposure of the rats to 13C-FA their blood was analyzed to det. the ratio between labeled and natural FA in blood and the total blood concn. of FA. With respect to sensitivity, with the applied method exogenous 13C-FA could have been detected in blood at a concn. approx. 1.5% of the endogenous FA blood concn. Exogenous 13C-FA was not detectable in the blood of rats either during or up to 30 min after the exposure. It was concluded that the inhalation of 13C-FA at 10 ppm for 6 h did not result in an increase of the total FA concn. in blood.

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    Jin, L.; Lorkiewicz, P.; Malovichko, M. V.; Bhatnagar, A.; Srivastava, S.; Conklin, D. J. Acetaldehyde induces an endothelium-dependent relaxation of superior mesenteric artery: Potential role in postprandial hyperemia. Front Physiol. 2019, 10, 1315,  DOI: 10.3389/fphys.2019.01315

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    Acetaldehyde Induces an Endothelium-Dependent Relaxation of Superior Mesenteric Artery: Potential Role in Postprandial Hyperemia

    Jin Lexiao; Jin Lexiao; Bhatnagar Aruni; Conklin Daniel J; Lorkiewicz Pawel; Malovichko Marina V; Bhatnagar Aruni; Srivastava Sanjay; Conklin Daniel J; Lorkiewicz Pawel; Bhatnagar Aruni; Srivastava Sanjay; Conklin Daniel J; Lorkiewicz Pawel; Malovichko Marina V; Bhatnagar Aruni; Srivastava Sanjay; Conklin Daniel J; Malovichko Marina V; Bhatnagar Aruni; Srivastava Sanjay; Conklin Daniel J

    Frontiers in physiology (2019), 10 (), 1315 ISSN:1664-042X.

    Acetaldehyde (AA) is a small, ubiquitous compound present in foods, beverages, as a gas phase combustion product, and also endogenously generated from metabolism as from ethanol (EtOH). Acetate is a short chain fatty acid derived from AA oxidation, and acetate levels were significantly higher in urine collected overnight with food provided ad libitum compared with urine collected after 9 h fasting. Feeding increases gastrointestinal blood flow, and thus, we explored the direct effects of AA (and acetate) in isolated murine superior mesenteric artery (SMA). Over the concentration range of 1-100 mM, AA strongly, and reversibly relaxed agonist-induced contractions of SMA including phenylephrine (PE), thromboxane A2 analog (U46,619) and high potassium (High K(+)) without toxicity. The sensitivity (EC50) but not the efficacy (>90% relaxation of PE-precontraction) of AA-induced relaxations was dependent on blood vessel (SMA was 3× more sensitive than aorta) and contractile agonist (PE EC50 = 3.3 ± 0.4 mM; U46,619 EC50 = 14.9 ± 1.5 mM; and High K(+) EC50 = 17.7 ± 0.5 mM) yet independent of circadian cycle and sex. The most sensitive component of the AA-induced relaxation was inhibited significantly by: (1) a mechanically impaired endothelium; (2) nitric oxide synthase (NOS) inhibitor (L-NAME); and (3) a guanylyl cyclase (GC) inhibitor (ODQ). Both acetate and EtOH stimulated much weaker relaxations in SMA than did AA, yet these relaxations were significantly inhibited by L-NAME as well. Neither EtOH nor acetate relaxed pre-contracted aorta. Although neither cyanamide, a non-specific aldehyde dehydrogenase (ALDH) enzyme inhibitor, nor Alda-1, a specific activator of ALDH2 activity, had any effect on either sensitivity or efficacy of AA-induced relaxation in SMA, cyanamide significantly blocked both EtOH- and acetate-induced relaxations in SMA implicating a role of ALDH activity in vasorelaxation. These data show that AA relaxes SMA via an endothelium- and NO-dependent mechanism indicating that AA may be one component of the complex post-prandial hyperemia reflex via vasodilatation of mesenteric vasculature.

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