Triphenyl Phosphate Alters Methyltransferase Expression and Induces Genome-Wide Aberrant DNA Methylation in Zebrafish Larvae

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1. 1

   van der Veen, I.; de Boer, J. Phosphorus Flame Retardants: Properties, Production, Environmental Occurrence, Toxicity and Analysis. Chemosphere 2012, 88 (10), 1119– 1153,  DOI: 10.1016/j.chemosphere.2012.03.067

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   Phosphorus flame retardants: properties, production, environmental occurrence, toxicity and analysis

   van der Veen, Ike; de Boer, Jacob

   Chemosphere (2012), 88 (10), 1119-1153CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

   A review. Since the ban on some brominated flame retardants (BFRs), phosphorus flame retardants (PFRs), which were responsible for 20% of the flame retardant (FR) consumption in 2006 in Europe, are often proposed as alternatives for BFRs. PFRs can be divided in three main groups, inorg., org. and halogen contg. PFRs. Most of the PFRs have a mechanism of action in the solid phase of burning materials (char formation), but some may also be active in the gas phase. Some PFRs are reactive FRs, which means they are chem. bound to a polymer, whereas others are additive and mixed into the polymer. The focus of this report is limited to the PFRs mentioned in the literature as potential substitutes for BFRs. The physico-chem. properties, applications and prodn. vols. of PFRs are given. Non-halogenated PFRs are often used as plasticisers as well. Limited information is available on the occurrence of PFRs in the environment. For tri-Ph phosphate (TPhP), tricresylphosphate (TCP), tris(2-chloroethyl)phosphate (TCEP), tris(chloropropyl)phosphate (TCPP), tris(1,3-dichloro-2-propyl)phosphate (TDCPP), and tetrekis(2-chlorethyl)dichloroisopentyldiphosphate (V6) a no. of studies have been performed on their occurrence in air, water and sediment, but limited data were found on their occurrence in biota. Concns. found for these PFRs in air were up to 47 μg m-3, in sediment levels up to 24 mg kg-1 were found, and in surface water concns. up to 379 ng L-1. In all these matrixes TCPP was dominant. Concns. found in dust were up to 67 mg kg-1, with TDCPP being the dominant PFR. PFR concns. reported were often higher than polybrominated diphenylether (PBDE) concns., and the human exposure due to PFR concns. in indoor air appears to be higher than exposure due to PBDE concns. in indoor air.Only the Cl-contg. PFRs are carcinogenic. Other neg. human health effects were found for Cl-contg. PFRs as well as for TCP, which suggest that those PFRs would not be suitable alternatives for BFRs. TPhP, diphenylcresylphosphate (DCP) and TCP would not be suitable alternatives either, because they are considered to be toxic to (aquatic) organisms. Diethylphosphinic acid is, just like TCEP, considered to be very persistent. From an environmental perspective, resorcinol-bis(diphenylphosphate) (RDP), bisphenol-A di-Ph phosphate (BADP) and melamine polyphosphate, may be suitable good substitutes for BFRs.Information on PFR anal. in air, water and sediment is limited to TCEP, TCPP, TPhP, TCP and some other organophosphate esters. For air sampling passive samplers have been used as well as solid phase extn. (SPE) membranes, SPE cartridges, and solid phase micro-extn. (SPME).For extn. of PFRs from water SPE is recommended, because this method gives good recoveries (67-105%) and acceptable relative std. deviations (RSDs) (<20%), and offers the option of online coupling with a detection system. For the extn. of PFRs from sediment microwave-assisted extn. (MAE) is recommended. The recoveries (78-105%) and RSDs (3-8%) are good and the method is faster and requires less solvent compared to other methods.For the final instrumental anal. of PFRs, gas chromatog.-flame photometric detection (GC-FPD), GC-nitrogen-phosphorus detection (NPD), GC-at. emission detection (AED), GC-mass spectrometry (MS) as well as liq. chromatog. (LC)-MS/MS and GC-Inductively-coupled plasma-MS (ICP-MS) are used. GC-ICP-MS is a promising method, because it provides much less complex chromatograms while offering the same recoveries and limits of detection (LOD) (instrumental LOD is 5-10 ng mL-1) compared to GC-NPD and GC-MS, which are frequently used methods for PFR anal. GC-MS offers a higher selectivity than GC-NPD and the possibility of using isotopically labeled compds. for quantification.
2. 2

   Mitro, S. D.; Dodson, R. E.; Singla, V.; Adamkiewicz, G.; Elmi, A. F.; Tilly, M. K.; Zota, A. R. Consumer Product Chemicals in Indoor Dust: A Quantitative Meta-Analysis of US Studies. Environ. Sci. Technol. 2016, 50 (19), 10661– 10672,  DOI: 10.1021/acs.est.6b02023

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3. 3

   Rantakokko, P.; Kumar, E.; Braber, J.; Huang, T.; Kiviranta, H.; Cequier, E.; Thomsen, C. Concentrations of Brominated and Phosphorous Flame Retardants in Finnish House Dust and Insights into Children’s Exposure. Chemosphere 2019, 223, 99– 107,  DOI: 10.1016/j.chemosphere.2019.02.027

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   Concentrations of brominated and phosphorous flame retardants in Finnish house dust and insights into children's exposure

   Rantakokko, Panu; Kumar, Eva; Braber, Joris; Huang, Taya; Kiviranta, Hannu; Cequier, Enrique; Thomsen, Cathrine

   Chemosphere (2019), 223 (), 99-107CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

   Brominated and phosphorous flame retardants (BFRs, PFRs) are added to household and consumer products to reduce their flammability. Some FRs are persistent in the environment and may have adverse health effects. As exposure indoors contributes significantly to total exposure, we wanted to est. the exposure of children (3 years of age) through dust ingestion, inhalation, and dermal absorption. We measured 17 BFRs and 10 PFRs in indoor dust, predicted their resp. concns. in the indoor air and assessed children's exposure. Among the BFRs, decabromodiphenyl ether (BDE-209) had highest median level in the dust (411 ng/g) followed by decabromodiphenyl ethane (DBDPE, 119 ng/g) and bis-ethylhexyl tetrabromophthalate (BEH-TEBP, 106 ng/g). Among the PFRs, trisbutoxyethyl phosphate (TBOEP) had the highest concn. (11100 ng/g) followed by tris(2-chloroisopropyl) phosphate (TCIPP, 1870 ng/g) and tri-Ph phosphate (TPHP, 773 ng/g). FR concn. in air predicted from dust concns. were within the interquartile range of exptl. data for 10/13 of BFRs and 4/8 of PFRs compared. Dust ingestion was the major route of exposure (75-99%) for higher mol. wt. BFRs, TBOEP and Ph based PFRs (73-77%). Inhalation was important for volatile BFRs like pentabromobenzene (PBB 71%) and pentabromotoluene (PBT 52%) and dermal exposure for volatile chlorinated PFRs (TCEP 84%, TCIPP 77%). Margins of Exposure (MoE) were calcd. as the ratio of total exposure to oral Ref. Dose (RfD). MoEs were lowest for TCEP (220), TBOEP (240) and TCIPP (830), and > 1000 for all other FRs. These MoEs imply no risk for Finnish children by the studied FRs.
4. 4

   Blum, A.; Behl, M.; Birnbaum, L. S.; Diamond, M. L.; Phillips, A.; Singla, V.; Sipes, N. S.; Stapleton, H. M.; Venier, M. Organophosphate Ester Flame Retardants: Are They a Regrettable Substitution for Polybrominated Diphenyl Ethers?. Environ. Sci. Technol. Lett. 2019, 6 (11), 638– 649,  DOI: 10.1021/acs.estlett.9b00582

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   Organophosphate Ester Flame Retardants: Are They a Regrettable Substitution for Polybrominated Diphenyl Ethers?

   Blum, Arlene; Behl, Mamta; Birnbaum, Linda S.; Diamond, Miriam L.; Phillips, Allison; Singla, Veena; Sipes, Nisha S.; Stapleton, Heather M.; Venier, Marta

   Environmental Science & Technology Letters (2019), 6 (11), 638-649CODEN: ESTLCU; ISSN:2328-8930. (American Chemical Society)

   A review to det. whether organophosphate ester flame retardants (OPFR) are a better choice (better alternative) than polybrominated di-Ph ether flame retardants (PBDE) by comparing the two over a range of properties is given. OPFR exposure is ubiquitous to humans and indoor/outdoor; they now often occur at higher concns. than PBDE peak exposure concns. Toxicity testing, epidemiol. study, and risk assessment data all suggest there are health concerns at current exposure levels for halogenated and non-halogenated OPFR. With the large no. of OPFR in use, producers can move toward healthier, safer products by developing innovative ways to reduce fire risks for electronics enclosures, upholstered furniture, building materials, and other consumer products with no added flame retardants. Topics discussed include: introduction; environmental behavior; indoor behavior and human exposure; toxicity and health effects; epidemiol. evidence; looking forward; supporting information (plasma bio-equiv. using high through-put toxicokinetic modeling).
5. 5

   Pantelaki, I.; Voutsa, D. Organophosphate Flame Retardants (OPFRs): A Review on Analytical Methods and Occurrence in Wastewater and Aquatic Environment. Sci. Total Environ. 2019, 649, 247– 263,  DOI: 10.1016/j.scitotenv.2018.08.286

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   Organophosphate flame retardants (OPFRs): A review on analytical methods and occurrence in wastewater and aquatic environment

   Pantelaki, Ioanna; Voutsa, Dimitra

   Science of the Total Environment (2019), 649 (), 247-263CODEN: STENDL; ISSN:0048-9697. (Elsevier B.V.)

   A review. Nowadays, there is an increasing concern for organophosphate flame retardants (OPFRs) due to high prodn. and use following the phase out and stringent regulation in the use of brominated flame retardants. OPFRs represent a group of compds. with a wide range in their polarity, soly. and persistence. OPFRs are widely used as flame retardants in various consumer products such as textiles, electronics, industrial materials and furniture to prevent the risk of fire. They are also utilized as plasticizers, antifoaming or anti-wear agents in lacquers, hydraulic fluids and floor polishing agents. The present review outlines the current state of knowledge regarding the anal. methodol. applied for their detn. in wastewater and aquatic environment as well as their occurrence in water, wastewater, sediments and sludge. Knowledge gaps and future perspectives have been identified, which include the elucidation of sources, pathways and fate of OPFRs in aquatic environment and possible risks.
6. 6

   Harrad, S.; De Wit, C. A.; Abdallah, M. A. E.; Bergh, C.; Björklund, J. A.; Covaci, A.; Darnerud, P. O.; De Boer, J.; Diamond, M.; Huber, S.; Leonards, P.; Mandalakis, M.; Östman, C.; Haug, L. S.; Thomsen, C.; Webster, T. F. Indoor Contamination with Hexabromocyclododecanes, Polybrominated Diphenyl Ethers, and Perfluoroalkyl Compounds: An Important Exposure Pathway for People?. Environ. Sci. Technol. 2010, 44 (9), 3221– 3231,  DOI: 10.1021/es903476t

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   Indoor contamination with hexabromocyclododecanes, polybrominated diphenyl ethers, and perfluoroalkyl compounds: An important exposure pathway for people?

   Harrad, Stuart; de Wit, Cynthia A.; Abdallah, Mohamed Abou-Elwafa; Bergh, Caroline; Bjorklund, Justina A.; Covaci, Adrian; Darnerud, Per Ola; de Boer, Jacob; Diamond, Miriam; Huber, Sandra; Leonards, Pim; Mandalakis, Manolis; Ostman, Conny; Haug, Line Smastuen; Thomsen, Cathrine; Webster, Thomas F.

   Environmental Science & Technology (2010), 44 (9), 3221-3231CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)

   A review on the importance of indoor contamination as a pathway of human exposure to hexabromocyclododecanes (HBCDs), polybrominated di-Ph ethers (PBDEs), and perfluoroalkyl compds. There is ample evidence of substantial contamination of indoor dust with these chems. and that their concns. in indoor air exceed substantially those outdoors. Studies examg. the relationship between body burden and exposure via indoor dust are inconsistent; while some indicate a link between body burdens and PBDE and HBCD exposure via dust ingestion, others find no correlation. Likewise, while concns. in indoor dust and human tissues are both highly skewed, this does not necessarily imply causality. Evidence suggests exposure via dust ingestion is higher for toddlers than adults. Research priorities include identifying means of reducing indoor concns. and indoor monitoring methods that provide the most "biol.-relevant" measures of exposure as well as monitoring a wider range of microenvironment categories. Other gaps include studies to improve understanding of the following: emission rates and mechanisms via which these contaminants migrate from products into indoor air and dust; relationships between indoor exposures and human body burdens; relevant physicochem. properties; the gastrointestinal uptake by humans of these chems. from indoor dust; and human dust ingestion rates.
7. 7

   Schreder, E. D.; Uding, N.; La Guardia, M. J. Inhalation a Significant Exposure Route for Chlorinated Organophosphate Flame Retardants. Chemosphere 2016, 150, 499– 504,  DOI: 10.1016/j.chemosphere.2015.11.084

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   Inhalation a significant exposure route for chlorinated organophosphate flame retardants

   Schreder, Erika D.; Uding, Nancy; La Guardia, Mark J.

   Chemosphere (2016), 150 (), 499-504CODEN: CMSHAF; ISSN:0045-6535. (Elsevier Ltd.)

   Chlorinated organophosphate flame retardants (ClOPFRs) are widely used as additive flame retardants in consumer products including furniture, children's products, building materials, and textiles. Tests of indoor media in homes, offices, and other environments have shown these compds. are released from products and have become ubiquitous indoor pollutants In house dust samples from Washington State, U. S. A., ClOPFRs were the flame retardants detected in the highest concns. Two ClOPFRs, tris(1,3-dichloro-2-propyl)phosphate (TDCPP or TDCIPP) and tris(2-chloroethyl)phosphate (TCEP), have been designated as carcinogens, and there is growing concern about the toxicity of the homolog tris(1-chloro-2-propyl)phosphate (TCPP or TCIPP). In response to concerns about exposure to these compds., the European Union and a no. of U. S. states have taken regulatory action to restrict their use in certain product categories. To better characterize exposure to ClOPFRs, inhalation exposure was assessed using active personal air samplers in Washington State with both respirable and inhalable particulate fractions collected to assess the likelihood particles penetrate deep into the lungs. Concns. of .sum.ClOPFRs (respirable and inhalable) ranged from 97.1 to 1190 ng m-3 (mean 426 ng m-3), with TCPP detected at the highest concns. In general, higher levels were detected in the inhalable particulate fraction. Total intake of ClOPFRs via the inhalation exposure route was estd. to exceed intake via dust ingestion, indicating that inhalation is an important route that should be taken into consideration in assessments of these compds.
8. 8

   Makinen, M. S. E.; Makinen, M. R. A.; Koistinen, J. T. B.; Pasanen, A. L.; Pasanen, P. O.; Kalliokoski, P. J.; Korpi, A. M. Respiratory and Dermal Exposure to Organophosphorus Flame Retardants and Tetrabromobisphenol A at Five Work Environments. Environ. Sci. Technol. 2009, 43 (3), 941– 947,  DOI: 10.1021/es802593t

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   Respiratory and Dermal Exposure to Organophosphorus Flame Retardants and Tetrabromobisphenol A at Five Work Environments

   Makinen, Maija S. E.; Makinen, Milja R. A.; Koistinen, Jaana T. B.; Pasanen, Anna-Liisa; Pasanen, Pertti O.; Kalliokoski, Pentti J.; Korpi, Anne M.

   Environmental Science & Technology (2009), 43 (3), 941-947CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)

   Organophosphorus compds. (OP) and tetrabromobisphenol A (TBBPA) are widely used as flame retardants (FR) in plastics, textiles, rubber, and building materials. Eight OP and TBBPA were quantified by gas chromatog.-mass spectrometry in air collected from a furniture workshop, a circuit board factory, 2 electronics dismantling facilities, a computer classroom, and offices and social premises. Also, dermal exposure was assessed with patch and hand wash samples at some workplaces. Tri-Ph phosphate, tris(2-chloroethyl)phosphate, and tris(2-chloroisopropyl)phosphate were typical workplace pollutants; TBBPA, tricresyl phosphate, tri-Bu phosphate, and tris(2-ethylhexyl)phosphate were rather site-specific. Highest geometric mean of total FR in air was measured in personal samples at the electronics dismantling facilities (2.9 and 3.8 μg/m3); stationary sample results from the other environments were 90-720 ng/m3. Stationary samples under-estd. personal exposure at 3 of 4 workplaces where comparisons were made. For the first time, dermal exposure was demonstrated at these occupational settings. The geometric mean of total FR levels in patch samples was 1.5-24 ng/cm2; 3.5-34 μg/2 hands in hand wash samples. The health effect of measured FR levels remains unknown.
9. 9

   Bajard, L.; Melymuk, L.; Blaha, L. Prioritization of Hazards of Novel Flame Retardants Using the Mechanistic Toxicology Information from ToxCast and Adverse Outcome Pathways. Environmental Sciences Europe. 2019, 31, 14,  DOI: 10.1186/s12302-019-0195-z

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    Guo, J.; Riley, K. W.; Durham, T.; Margolis, A. E.; Wang, S.; Perera, F.; Herbstman, J. B. Association Studies of Environmental Exposures, DNA Methylation and Children’s Cognitive, Behavioral, and Mental Health Problems. Front. Genet. 2022, 13, 871820,  DOI: 10.3389/fgene.2022.871820

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    Omichessan, H.; Perduca, V.; Polidoro, S.; Kvaskoff, M.; Truong, T.; Cano-Sancho, G.; Antignac, J. P.; Baglietto, L.; Mancini, F. R.; Severi, G. Associations between Plasma Levels of Brominated Flame Retardants and Methylation of DNA from Peripheral Blood: A Cross-Sectional Study in a Cohort of French Women. Environ. Res. 2022, 210, 112788,  DOI: 10.1016/j.envres.2022.112788

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    Kim, S.; Cho, Y. H.; Won, S.; Ku, J. L.; Moon, H. B.; Park, J.; Choi, G.; Kim, S.; Choi, K. Maternal Exposures to Persistent Organic Pollutants Are Associated with DNA Methylation of Thyroid Hormone-Related Genes in Placenta Differently by Infant Sex. Environ. Int. 2019, 130, 104956,  DOI: 10.1016/j.envint.2019.104956

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    Maternal exposures to persistent organic pollutants are associated with DNA methylation of thyroid hormone-related genes in placenta differently by infant sex

    Kim, Sujin; Cho, Yoon Hee; Won, Sungho; Ku, Ja-Lok; Moon, Hyo-Bang; Park, Jeongim; Choi, Gyuyeon; Kim, Sungkyoon; Choi, Kyungho

    Environment International (2019), 130 (), 104956CODEN: ENVIDV; ISSN:0160-4120. (Elsevier Ltd.)

    Exposure to persistent org. pollutants (POPs) during pregnancy is assocd. with a disruption in thyroid hormone balance. The placenta serves as an important environment for fetal development and also regulates thyroid hormone supply to the fetus. However, epigenetic changes of thyroid regulating genes in placenta have rarely been studied. This study was conducted to evaluate the assocn. between several POP concns. in maternal serum and DNA methylation of thyroid hormone-related genes in the placenta. The placenta samples were collected from 106 Korean mother at delivery, and the promoter methylation of the placental genes was measured by a bisulfite pyrosequencing. The deiodinase type 3 (DIO3), monocarboxylate transporter 8 (MCT8), and transthyretin (TTR) genes were selected as the target genes as they play an important role in the regulation of fetal thyroid balance. Because people are exposed to multiple chems. at the same time, a multiple-POP model using principal component anal. (PCA) was applied to evaluate the assocn. between the multiple POPs exposure and the epigenetic change in placenta. In addn., a single-POP model which includes one chem. each in the statistical model for assocn. was conducted. Based on the single-POP models, serum concns. of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and brominated di-Ph ether-47 (BDE-47) were significantly assocd. with an increase in placental DIO3 methylation, but only among female infants. Among male infants, a pos. assocn. between serum p,p'-DDT and MCT8 methylation level was found. According to the multiple-POP models, serum DDTs were pos. assocd. with DIO3 methylation in the placenta of female infants, while a pos. assocn. with MCT8 methylation was obsd. in those of the male infants. Our observation showed that in utero exposure to DDTs may influence the DNA methylation of DIO3 and MCT8 genes in the placenta, in a sexually dimorphic manner. These alterations in placental epigenetic regulation may in part explain the thyroid hormone disruption obsd. among the newborns or infants followed by in utero exposure to POPs.
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    Soubry, A.; Hoyo, C.; Butt, C. M.; Fieuws, S.; Price, T. M.; Murphy, S. K.; Stapleton, H. M. Human Exposure to Flame-Retardants Is Associated with Aberrant DNA Methylation at Imprinted Genes in Sperm. Environ. Epigenetics 2017, 3 (1), 1– 13,  DOI: 10.1093/eep/dvx003

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    Lind, L.; Penell, J.; Luttropp, K.; Nordfors, L.; Syvänen, A.-C.; Axelsson, T.; Salihovic, S.; van Bavel, B.; Fall, T.; Ingelsson, E.; Lind, P. M. Global DNA Hypermethylation Is Associated with High Serum Levels of Persistent Organic Pollutants in an Elderly Population. Environ. Int. 2013, 59, 456– 461,  DOI: 10.1016/j.envint.2013.07.008

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    Bird, A. DNA Methylation Patterns and Epigenetic Memory. Genes Dev. 2002, 16, 6– 21,  DOI: 10.1101/gad.947102

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    DNA methylation patterns and epigenetic memory

    Bird, Adrian

    Genes & Development (2002), 16 (1), 6-21CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)

    There is no expanded citation for this reference.
16. 16

    Edwards, J. R.; Yarychkivska, O.; Boulard, M.; Bestor, T. H. DNA Methylation and DNA Methyltransferases. Epigenetics and Chromatin 2017, 10, 23,  DOI: 10.1186/s13072-017-0130-8

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    Ito, S.; Shen, L.; Dai, Q.; Wu, S. C.; Collins, L. B.; Swenberg, J. A.; He, C.; Zhang, Y. Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine. Science (80-.). 2011, 333 (6047), 1300– 1303,  DOI: 10.1126/science.1210597

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    Tet Proteins Can Convert 5-Methylcytosine to 5-Formylcytosine and 5-Carboxylcytosine

    Ito, Shinsuke; Shen, Li; Dai, Qing; Wu, Susan C.; Collins, Leonard B.; Swenberg, James A.; He, Chuan; Zhang, Yi

    Science (Washington, DC, United States) (2011), 333 (6047), 1300-1303CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

    5-Methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addn. to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymic activity-dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivs. in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidn. followed by decarboxylation.
18. 18

    Agrawal, A.; Murphy, R. F.; Agrawal, D. K. DNA Methylation in Breast and Colorectal Cancers. Mod. Pathol. 2007, 20 (7), 711– 721,  DOI: 10.1038/modpathol.3800822

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    DNA methylation in breast and colorectal cancers

    Agrawal, Anshu; Murphy, Richard F.; Agrawal, Devendra K.

    Modern Pathology (2007), 20 (7), 711-721CODEN: MODPEO; ISSN:0893-3952. (Nature Publishing Group)

    A review. DNA methylation is one of several epigenetic changes obsd. in cells. Aberrant methylation of tumor suppressor genes, proto-oncogenes, and vital cell cycle genes has led many scientists to investigate the underlying cellular mechanisms of DNA methylation under normal and pathol. conditions. Although DNA methylation is necessary for normal mammalian embryogenesis, both hypo- and hypermethylation of DNA are frequently obsd. in carcinogenesis and other pathol. disorders. DNA hypermethylation silences the transcription of many tumor suppressor genes, resulting in immortalization of tumor cells. The reverse process, demethylation and restoration of normal functional expression of genes, is augmented by DNA methylation inhibitors. Recent studies suggest that DNA hypomethylation may also control gene expression and chromosomal stability. However, the roles of and relationship between hypomethylation and hypermethylation are not well understood. This review provides a brief overview of the mechanism of DNA methylation, its relationship to extrinsic stimulation including dietary intake and aging, and of abnormally methylated DNA in breast and colorectal cancers, which could be used as prognostic and diagnostic markers.
19. 19

    Eden, A.; Gaudet, F.; Waghmare, A.; Jaenisch, R. Chromosomal Instability and Tumors Promoted by DNA Hypomethylation. Science 2003, 300 (5618), 455,  DOI: 10.1126/science.1083557

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    Jones, P. A.; Baylin, S. B. The Fundamental Role of Epigenetic Events in Cancer. Nat. Rev. Genet. 2002, 3 (6), 415– 428,  DOI: 10.1038/nrg816

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    The fundamental role of epigenetic events in cancer

    Jones, Peter A.; Baylin, Stephen B.

    Nature Reviews Genetics (2002), 3 (6), 415-428CODEN: NRGAAM; ISSN:1471-0056. (Nature Publishing Group)

    A review. Patterns of DNA methylation and chromatin structure are profoundly altered in neoplasia and include genome-wide losses of, and regional gains in, DNA methylation. The recent explosion in our knowledge of how chromatin organization modulates gene transcription has further highlighted the importance of epigenetic mechanisms in the initiation and progression of human cancer. These epigenetic changes - in particular, aberrant promoter hypermethylation that is assocd. with inappropriate gene silencing - affect virtually every step in tumor progression. In this review, we discuss these epigenetic events and the mol. alterations that might cause them and/or underlie altered gene expression in cancer.
21. 21

    Kumar, S.; Chinnusamy, V.; Mohapatra, T. Epigenetics of Modified DNA Bases: 5-Methylcytosine and Beyond. Front. Genet. 2018, 9, 429871  DOI: 10.3389/fgene.2018.00640

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    Maunakea, A. K.; Nagarajan, R. P.; Bilenky, M.; Ballinger, T. J.; D'Souza, C.; Fouse, S. D.; Johnson, B. E.; Hong, C.; Nielsen, C.; Zhao, Y.; Turecki, G.; Delaney, A.; Varhol, R.; Thiessen, N.; Shchors, K.; Heine, V. M.; Rowitch, D. H.; Xing, X.; Fiore, C.; Schillebeeckx, M.; Jones, S. J. M.; Haussler, D.; Marra, M. A.; Hirst, M.; Wang, T.; Costello, J. F. Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters. Nature 2010, 466 (7303), 253– 257,  DOI: 10.1038/nature09165

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    Conserved role of intragenic DNA methylation in regulating alternative promoters

    Maunakea, Alika K.; Nagarajan, Raman P.; Bilenky, Mikhail; Ballinger, Tracy J.; D'Souza, Cletus; Fouse, Shaun D.; Johnson, Brett E.; Hong, Chibo; Nielsen, Cydney; Zhao, Yongjun; Turecki, Gustavo; Delaney, Allen; Varhol, Richard; Thiessen, Nina; Shchors, Ksenya; Heine, Vivi M.; Rowitch, David H.; Xing, Xiaoyun; Fiore, Chris; Schillebeeckx, Maximiliaan; Jones, Steven J. M.; Haussler, David; Marra, Marco A.; Hirst, Martin; Wang, Ting; Costello, Joseph F.

    Nature (London, United Kingdom) (2010), 466 (7303), 253-257CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped anal. of gene expression (CAGE) expts. also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resoln. coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homolog demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
23. 23

    Tekola-Ayele, F.; Zeng, X.; Ouidir, M.; Workalemahu, T.; Zhang, C.; Delahaye, F.; Wapner, R. DNA Methylation Loci in Placenta Associated with Birthweight and Expression of Genes Relevant for Early Development and Adult Diseases. Clin. Epigenetics 2020, 12 (1), 78,  DOI: 10.1186/s13148-020-00873-x

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    Tobi, E. W.; Slieker, R. C.; Luijk, R.; Dekkers, K. F.; Stein, A. D.; Xu, K. M.; Slagboom, P. E.; van Zwet, E. W.; Lumey, L. H.; Heijmans, B. T. DNA Methylation as a Mediator of the Association between Prenatal Adversity and Risk Factors for Metabolic Disease in Adulthood. Sci. Adv. 2018, 4 (1), eaao4364,  DOI: 10.1126/sciadv.aao4364

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    Lapehn, S.; Paquette, A. G. The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis. Curr. Environ. Heal. Reports 2022, 9 (3), 490– 501,  DOI: 10.1007/s40572-022-00354-8

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    Keil, K. P.; Lein, P. J. DNA Methylation: A Mechanism Linking Environmental Chemical Exposures to Risk of Autism Spectrum Disorders?. Environmental Epigenetics 2016, 2, dvv012,  DOI: 10.1093/eep/dvv012

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    Yin, R.; Mo, J.; Dai, J.; Wang, H. Nickel(II) Inhibits Tet-Mediated 5-Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II). ACS Chem. Biol. 2017, 12 (6), 1494– 1498,  DOI: 10.1021/acschembio.7b00261

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    27

    Nickel(II) Inhibits Tet-Mediated 5-Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II)

    Yin, Ruichuan; Mo, Jiezhen; Dai, Jiayin; Wang, Hailin

    ACS Chemical Biology (2017), 12 (6), 1494-1498CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)

    Ten-eleven translocation (Tet) family proteins are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that regulate the dynamics of DNA methylation by catalyzing the oxidn. of DNA 5-methylcytosine (5mC). To exert physiol. important functions, redox-active iron chelated in the catalytic center of Tet proteins directly involves the oxidn. of the multiple substrates. To understand the function and interaction network of Tet dioxygenases, it is interesting to obtain high affinity and a specific inhibitor. Surprisingly, here we found that natural Ni(II) ion can bind to the Fe(II)-chelating motif (HXD) with an affinity of 7.5-fold as high as Fe(II). Consistently, we further found that Ni(II) ion can displace the cofactor Fe(II) of Tet dioxygenases and inhibit Tet-mediated 5mC oxidn. activity with an estd. IC50 of 1.2 μM. Essentially, Ni(II) can be used as a high affinity and selective inhibitor to explore the function and dynamics of Tet proteins.
28. 28

    Zhao, B.; Yang, Y.; Wang, X.; Chong, Z.; Yin, R.; Song, S. H.; Zhao, C.; Li, C.; Huang, H.; Sun, B. F.; Wu, D.; Jin, K. X.; Song, M.; Zhu, B. Z.; Jiang, G.; Rendtlew Danielsen, J. M.; Xu, G. L.; Yang, Y. G.; Wang, H. Redox-Active Quinones Induces Genome-Wide DNA Methylation Changes by an Iron-Mediated and Tet-Dependent Mechanism. Nucleic Acids Res. 2014, 42 (3), 1593– 1605,  DOI: 10.1093/nar/gkt1090

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29. 29

    Li, Z.; Lyu, C.; Ren, Y.; Wang, H. Role of TET Dioxygenases and DNA Hydroxymethylation in Bisphenols-Stimulated Proliferation of Breast Cancer Cells. Environ. Health Perspect. 2020, 128 (2), 27008,  DOI: 10.1289/EHP5862

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    29

    Role of TET dioxygenases and DNA hydroxymethylation in bisphenols-stimulated proliferation of breast cancer cells

    Li, Zhe; Cong, Lyu; Ren, Yun; Wang, Hailin

    Environmental Health Perspectives (2020), 128 (2), 027008CODEN: EVHPAZ; ISSN:1552-9924. (U. S. Department of Health and Human Services, National Institutes of Health)

    BACKGROUND: Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor targeting estrogen receptors (ERs), has been implicated in the promotion of breast cancer. Perinatal exposure of BPA could induce longitudinal alteration of DNA hydroxymethylation in imprinted loci of mouse blood cells. To date, no data has been reported on the effects of BPA on DNA hydroxymethylation in breast cells. Therefore, we asked whether BPA can induce DNA hydroxymethylation change in human breast cells. Given that dysregulated epigenetic DNA hydroxymethylation is obsd. in vari ous cancers, we wondered how DNA hydroxymethylation modulates cancer development, and specifically, whether and how BPA and its analogs pro mote breast cancer development via DNA hydroxymethylation. OBJECTIVES: We aimed to explore the interplay of the estrogenic activity of bisphenols at environmental exposure dose levels with TET dioxygenase-catalyzed DNA hydroxymethylation and to elucidate their roles in the proliferation of ER+ breast cancer cells as stimulated by environmentally relevant bisphenols. METHODS: Human MCF-7 and T47D cell lines were used as ER-dependent breast cell proliferation models, and the human MDA-MB-231 cell line was used as an ER-independent breast cell model. These cells were treated with BPA or bisphenol S (BPS) to examine BPA/BPS-related proliferation. Ultra-high performance liq. chromatog. -tandem mass spectrometry (UHPLC-MS/MS) and enzyme-linked immunosorbent assays (ELISAs) were used to detect DNA hydroxymethylation. Crispr/Cas9 and RNA interference technologies, quant. polymerase chain reaction (qPCR), and Western blot analyses were used to evaluate the expression and function of genes. Co-immunopptn. (Co-IP), bisulfite sequencing-PCR (BSP), and chromatin immunopptn.-qPCR (ChIP-qPCR) were used to identify the interactions of target proteins. RESULTS: We measured higher proliferation in ER+ breast cancer cells treated with BPA or its replacement, BPS, accompanied by an ERa-dependent decrease in genomic DNA hydroxymethylation. The results of our overexpression, knockout, knockdown, and inhibition expts. suggested that TET2-catalyzed DNA hydroxymethylation played a suppressive role in BPA/BPS-stimulated cell proliferation. On the other hand, we obsd. that TET2 was neg. regulated by the activation of ERα (dimerized and phosphorylated), which was also induced by BPA/BPS binding. Instead of a direct interaction between TET2 and ERa, data of our Co-IP, BSP, and ChIP-qPCR expts. indicated that the activated ERa increased the DNA methyltransferase (DNMT)-mediated promoter methylation of TET2, leading to an inhibition of the TET2 expression and DNA hydroxymethylation. CONCLUSIONS: We identified a new feedback circuit of ERα activation -DNMT-TET2-DNA hydroxymethylation in ER+ breast cancer cells and uncovered a pivotal role of TET2-mediated DNA hydroxymethylation in modulating BPA/BPS-stimulated proliferation. Moreover, to our knowledge, we for the first time established a linkage among chem. exposure, DNA hydroxymethylation, and tumor-assocd. proliferation. These findings further clarify the estrogenic activity of BPA/BPS and its profound implications for the regulation of epigenetic DNA hydroxymethylation and cell proliferation.
30. 30

    Yin, R.; Mao, S. Q.; Zhao, B.; Chong, Z.; Yang, Y.; Zhao, C.; Zhang, D.; Huang, H.; Gao, J.; Li, Z.; Jiao, Y.; Li, C.; Liu, S.; Wu, D.; Gu, W.; Yang, Y. G.; Xu, G. L.; Wang, H. Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals. J. Am. Chem. Soc. 2013, 135 (28), 10396– 10403,  DOI: 10.1021/ja4028346

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    Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

    Yin, Ruichuan; Mao, Shi-Qing; Zhao, Bailin; Chong, Zechen; Yang, Ying; Zhao, Chao; Zhang, Dapeng; Huang, Hua; Gao, Juan; Li, Zheng; Jiao, Yan; Li, Cuiping; Liu, Shengquan; Wu, Danni; Gu, Weikuan; Yang, Yun-Gui; Xu, Guo-Liang; Wang, Hailin

    Journal of the American Chemical Society (2013), 135 (28), 10396-10403CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    DNA hydroxymethylation and its mediated DNA demethylation are crit. for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidn. of 5-methylcytosine (5MC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidn.-resistant derivs., we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe2+. Other strong reducing chems. do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5MC oxidn. products, particularly 5-formyl cytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5MC (∼40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5MC oxidn. nor the overall level of 5MC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5MC oxidn. and DNA demethylation are also obsd. in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications.
31. 31

    Lillycrop, K. A.; Burdge, G. C. Epigenetic Changes in Early Life and Future Risk of Obesity. Int. J. Obes. 2011, 35 (1), 72– 83,  DOI: 10.1038/ijo.2010.122

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    Kamstra, J. H.; Aleström, P.; Kooter, J. M.; Legler, J. Zebrafish as a Model to Study the Role of DNA Methylation in Environmental Toxicology. Environ. Sci. Pollut. Res. 2015, 22 (21), 16262– 16276,  DOI: 10.1007/s11356-014-3466-7

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    Williams, T. D.; Mirbahai, L.; Chipman, J. K. The Toxicological Application of Transcriptomics and Epigenomics in Zebrafish and Other Teleosts. Brief. Funct. Genomics 2014, 13 (2), 157– 171,  DOI: 10.1093/bfgp/elt053

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    Water Quality - Determination of the Acute Lethal Toxicity of Substances to a Freshwater Fish (Brachydanio Rerio Hamilton-Buchanan (Teleostei, Cyprinidae)) - Part 1: Static Method; ISO, 2001.

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    Kimmel, C. B.; Ballard, W. W.; Kimmel, S. R.; Ullmann, B.; Schilling, T. F. Stages of Embryonic Development of the Zebrafish. Dev. Dyn. 1995, 203 (3), 253– 310,  DOI: 10.1002/aja.1002030302

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    Stages of embryonic development of the zebrafish

    Kimmel C B; Ballard W W; Kimmel S R; Ullmann B; Schilling T F

    Developmental dynamics : an official publication of the American Association of Anatomists (1995), 203 (3), 253-310 ISSN:1058-8388.

    We describe a series of stages for development of the embryo of the zebrafish, Danio (Brachydanio) rerio. We define seven broad periods of embryogenesis--the zygote, cleavage, blastula, gastrula, segmentation, pharyngula, and hatching periods. These divisions highlight the changing spectrum of major developmental processes that occur during the first 3 days after fertilization, and we review some of what is known about morphogenesis and other significant events that occur during each of the periods. Stages subdivide the periods. Stages are named, not numbered as in most other series, providing for flexibility and continued evolution of the staging series as we learn more about development in this species. The stages, and their names, are based on morphological features, generally readily identified by examination of the live embryo with the dissecting stereomicroscope. The descriptions also fully utilize the optical transparancy of the live embryo, which provides for visibility of even very deep structures when the embryo is examined with the compound microscope and Nomarski interference contrast illumination. Photomicrographs and composite camera lucida line drawings characterize the stages pictorially. Other figures chart the development of distinctive characters used as staging aid signposts.
36. 36

    Alzualde, A.; Behl, M.; Sipes, N. S.; Hsieh, J. H.; Alday, A.; Tice, R. R.; Paules, R. S.; Muriana, A.; Quevedo, C. Toxicity Profiling of Flame Retardants in Zebrafish Embryos Using a Battery of Assays for Developmental Toxicity, Neurotoxicity, Cardiotoxicity and Hepatotoxicity toward Human Relevance. Neurotoxicol. Teratol. 2018, 70, 40– 50,  DOI: 10.1016/j.ntt.2018.10.002

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    Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance

    Alzualde, Ainhoa; Behl, Mamta; Sipes, Nisha S.; Hsieh, Jui-Hua; Alday, Aintzane; Tice, Raymond R.; Paules, Richard S.; Muriana, Arantza; Quevedo, Celia

    Neurotoxicology and Teratology (2018), 70 (), 40-50CODEN: NETEEC; ISSN:0892-0362. (Elsevier Inc.)

    Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment. We utilized zebrafish embryos to assess developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity, of eight replacement OPFRs: (tri-Ph phosphate [TPHP], isopropylated Ph phosphate [IPP], 2-ethylhexyl di-Ph phosphate [EHDP], tert-butylated Ph di-Ph phosphate [BPDP], tri-Me Ph phosphate [TMPP], isodecyl di-Ph phosphate [IDDP], tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl) phosphate [TCEP]) and two BFRs (3,3',5,5- tetrabromobisphenol A [TBBPA] and 2,24,4brominated di-Ph ether [BDE-47]). To det. potential effects on teratogenicity, embryos were exposed to flame retardants (FRs) at 4 h post fertilization (hpf) to 4 days post fertilization (dpf) and morphol. alterations and corresponding survival were evaluated at 2 and 4 dpf. Internal concns. were measured in larvae used in this assay by liq. chromatog.-mass spectrometry. Locomotor activity was assessed in larvae treated for 48 h (from 3 dpf to 5 dpf), followed by hepatotoxicity evaluation. Finally, alterations in heart rate and rhythmicity were assessed to det. cardiotoxicity in 48 hpf embryos exposed to compds. for 3 h. Results suggest that several OPFRs (BPDP, EHDP; IPP, TMPP; TPHP and TDCIPP) produced adverse effects in multiple target organs at concns. comparable to the two BFRs. As these OPFRs have the capacity to disrupt an integrated vertebrate model, they potentially have the capacity to affect mammalian biol. Then, we compared the lowest effective levels (LEL) in zebrafish with estd. or measured human plasma concns. using biomonitoring data (human plasma, breast milk, handwipe samples and house dust) and a high throughput toxicokinetic (HTTK) model. Results indicate that for some compds., the nominal LELs were within the range of human exposures, while internal LELs in zebrafish are above internal exposures in humans. These findings demonstrate the value of the zebrafish model as a relevant screening tool and support the need for further hazard characterization of the OPFRs.
37. 37

    Livak, K. J.; Schmittgen, T. D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2-ΔΔCT Method. Methods 2001, 25 (4), 402– 408,  DOI: 10.1006/meth.2001.1262

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    Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method

    Livak, Kenneth J.; Schmittgen, Thomas D.

    Methods (San Diego, CA, United States) (2001), 25 (4), 402-408CODEN: MTHDE9; ISSN:1046-2023. (Academic Press)

    The two most commonly used methods to analyze data from real-time, quant. PCR expts. are abs. quantification and relative quantification. Abs. quantification dets. the input copy no., usually by relating the PCR signal to a std. curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2-ΔΔCT method is a convenient way to analyze the relative changes in gene expression from real-time quant. PCR expts. The purpose of this report is to present the derivation, assumptions, and applications of the 2-ΔΔCT method. In addn., we present the derivation and applications of two variations of the 2-ΔΔCT method that may be useful in the anal. of real-time, quant. PCR data. (c) 2001 Academic Press.
38. 38

    Bolger, A. M.; Lohse, M.; Usadel, B. Trimmomatic: A Flexible Trimmer for Illumina Sequence Data. Bioinformatics 2014, 30 (15), 2114– 2120,  DOI: 10.1093/bioinformatics/btu170

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    Trimmomatic: a flexible trimmer for Illumina sequence data

    Bolger, Anthony M.; Lohse, Marc; Usadel, Bjoern

    Bioinformatics (2014), 30 (15), 2114-2120CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)

    Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both ref.-based and ref.-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.phppage=trimmomatic Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.
39. 39

    Volz, D. C.; Leet, J. K.; Chen, A.; Stapleton, H. M.; Katiyar, N.; Kaundal, R.; Yu, Y.; Wang, Y. Tris(1,3-Dichloro-2-Propyl)Phosphate Induces Genome-Wide Hypomethylation within Early Zebrafish Embryos. Environ. Sci. Technol. 2016, 50 (18), 10255– 10263,  DOI: 10.1021/acs.est.6b03656

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    Shafique, S.; Wolpert, S. H.; Philbrook, N. A.; Winn, L. M. Gestational Exposure to Triphenyl Phosphate Induces Epigenetic Modifications in C57Bl/6 Fetal Liver. Birth Defects Res. 2023, 115 (3), 338– 347,  DOI: 10.1002/bdr2.2121

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    Lou, S.; Lee, H.-M.; Qin, H.; Li, J.-W.; Gao, Z.; Liu, X.; Chan, L. L; KL Lam, V.; So, W.-Y.; Wang, Y.; Lok, S.; Wang, J.; Ma, R. C.; Tsui, S. K.-W.; Chan, J. C.; Chan, T.-F.; Yip, K. Y Whole-Genome Bisulfite Sequencing of Multiple Individuals Reveals Complementary Roles of Promoter and Gene Body Methylation in Transcriptional Regulation. Genome Biol. 2014, 15 (7), 408,  DOI: 10.1186/s13059-014-0408-0

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    Yang, X.; Han, H.; DeCarvalho, D. D.; Lay, F. D.; Jones, P. A.; Liang, G. Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer. Cancer Cell 2014, 26 (4), 577– 590,  DOI: 10.1016/j.ccr.2014.07.028

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    Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer

    Yang, Xiaojing; Han, Han; De Carvalho, Daniel D.; Lay, Fides D.; Jones, Peter A.; Liang, Gangning

    Cancer Cell (2014), 26 (4), 577-590CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)

    DNA methylation in promoters is well known to silence genes and is the presumed therapeutic target of methylation inhibitors. Gene body methylation is pos. correlated with expression, yet its function is unknown. We show that 5-aza-2'-deoxycytidine treatment not only reactivates genes but decreases the overexpression of genes, many of which are involved in metabolic processes regulated by c-MYC. Downregulation is caused by DNA demethylation of the gene bodies and restoration of high levels of expression requires remethylation by DNMT3B. Gene body methylation may, therefore, be an unexpected therapeutic target for DNA methylation inhibitors, resulting in the normalization of gene overexpression induced during carcinogenesis. Our results provide direct evidence for a causal relationship between gene body methylation and transcription.
43. 43

    Rauch, T. A.; Wu, X.; Zhong, X.; Riggs, A. D.; Pfeifer, G. P. A Human B Cell Methylome at 100-Base Pair Resolution. Proc. Natl. Acad. Sci. U. S. A. 2009, 106 (3), 671– 678,  DOI: 10.1073/pnas.0812399106

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    Ball, M. P.; Li, J. B.; Gao, Y.; Lee, J. H.; Leproust, E. M.; Park, I. H.; Xie, B.; Daley, G. Q.; Church, G. M. Targeted and Genome-Scale Strategies Reveal Gene-Body Methylation Signatures in Human Cells. Nat. Biotechnol. 2009, 27 (4), 361– 368,  DOI: 10.1038/nbt.1533

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    Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells

    Ball, Madeleine P.; Li, Jin Billy; Gao, Yuan; Lee, Je-Hyuk; Le Proust, Emily M.; Park, In-Hyun; Xie, Bin; Daley, George Q.; Church, George M.

    Nature Biotechnology (2009), 27 (4), 361-368CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)

    Studies of epigenetic modifications would benefit from improved methods for high-throughput methylation profiling. We introduce two complementary approaches that use next-generation sequencing technol. to detect cytosine methylation. In the first method, we designed ∼10,000 bisulfite padlock probes to profile ∼7000 CpG locations distributed over the ENCODE pilot project regions and applied them to human B-lymphocytes, fibroblasts and induced pluripotent stem cells. This unbiased choice of targets takes advantage of existing expression and chromatin immunopptn. data and enabled us to observe a pattern of low promoter methylation and high gene-body methylation in highly expressed genes. The second method, methyl-sensitive cut counting, generated nontargeted genome-scale data for ∼1.4 million HpaII sites in the DNA of B-lymphocytes and confirmed that gene-body methylation in highly expressed genes is a consistent phenomenon throughout the human genome. Our observations highlight the usefulness of techniques that are not inherently or intentionally biased towards particular subsets like CpG islands or promoter regions.
45. 45

    Arechederra, M.; Daian, F.; Yim, A.; Bazai, S. K.; Richelme, S.; Dono, R.; Saurin, A. J.; Habermann, B. H.; Maina, F. Hypermethylation of Gene Body CpG Islands Predicts High Dosage of Functional Oncogenes in Liver Cancer. Nat. Commun. 2018, 9 (1), 1– 16,  DOI: 10.1038/s41467-018-05550-5

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    Wang, D.; Yan, S.; Yan, J.; Teng, M.; Meng, Z.; Li, R.; Zhou, Z.; Zhu, W. Effects of Triphenyl Phosphate Exposure during Fetal Development on Obesity and Metabolic Dysfunctions in Adult Mice: Impaired Lipid Metabolism and Intestinal Dysbiosis. Environ. Pollut. 2019, 246, 630– 638,  DOI: 10.1016/j.envpol.2018.12.053

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    Effects of triphenyl phosphate exposure during fetal development on obesity and metabolic dysfunctions in adult mice: Impaired lipid metabolism and intestinal dysbiosis

    Wang, Dezhen; Yan, Sen; Yan, Jin; Teng, Miaomiao; Meng, Zhiyuan; Li, Ruisheng; Zhou, Zhiqiang; Zhu, Wentao

    Environmental Pollution (Oxford, United Kingdom) (2019), 246 (), 630-638CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    Previous in vitro studies have implied that tri-Ph phosphate (TPHP) may act as an obesogen. However, its specific contributions to the progression of obesity and related metabolic diseases are still unclear in vivo in mice. In this study, we evaluated the effects of in utero and lactational exposure to three doses of TPHP (10, 100, and 1000μg/kg BW) on obesity and metabolic dysfunctions in adult male mice fed a low-fat diet (LFD) or high-fat diet (HFD), by examg. body wt., liver wt., histopathol., blood biochem., gene expression, and gut microbiota compns. and metabolic functions. Results showed that TPHP exposure led to increased body wt., liver wt., fat mass, hepatic steatosis, impaired glucose homeostasis, and insulin resistance, and mRNA levels of genes involved in lipid metab., esp. lipogenesis and lipid accumulation, were significantly altered by TPHP treatment. Gas chromatog.-mass spectrometry (GC-MS) anal. further supported the changes in fatty acid compn. Intestinal flora measurements by 16S rRNA gene sequencing and 1H NMR based fecal metabolomics indicated that TPHP treatment modulated gut microbiome compn. and influenced host-gut co-metab., esp. for bile acids and short chain fatty acids (SCFAs). These results suggest that fetal exposure to TPHP can promote the development of obesity and metabolic dysfunctions in adult mice.
47. 47

    Dahlman, I.; Sinha, I.; Gao, H.; Brodin, D.; Thorell, A.; Rydén, M.; Andersson, D. P.; Henriksson, J.; Perfilyev, A.; Ling, C.; Dahlman-Wright, K.; Arner, P. The Fat Cell Epigenetic Signature in Post-Obese Women Is Characterized by Global Hypomethylation and Differential DNA Methylation of Adipogenesis Genes. Int. J. Obes. 2015, 39 (6), 910– 919,  DOI: 10.1038/ijo.2015.31

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    Liu, H.; Cui, H.; Huang, Y.; Gao, S.; Tao, S.; Hu, J.; Wan, Y. Xenobiotics Targeting Cardiolipin Metabolism to Promote Thrombosis in Zebrafish. Environ. Sci. Technol. 2021, 55 (6), 3855– 3866,  DOI: 10.1021/acs.est.0c08068

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    Leow, S. C.; Poschmann, J.; Too, P. G.; Yin, J.; Joseph, R.; McFarlane, C.; Dogra, S.; Shabbir, A.; Ingham, P. W.; Prabhakar, S.; Leow, M. K. S.; Lee, Y. S.; Ng, K. L.; Chong, Y. S.; Gluckman, P. D.; Stünkel, W. The Transcription Factor SOX6 Contributes to the Developmental Origins of Obesity by Promoting Adipogenesis. Dev. 2016, 143 (6), 950– 961,  DOI: 10.1242/dev.131573

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    Lee, J.; Kim, M.-S. The Role of GSK3 in Glucose Homeostasis and the Development of Insulin Resistance. Diabetes Res. Clin. Pract. 2007, 77 (3), S49– S57,  DOI: 10.1016/j.diabres.2007.01.033

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    Totsuka, Y.; Tabuchi, M.; Kojima, I.; Eto, Y.; Shibai, H.; Ogata, E. Stimulation of Insulin Secretion by Transforming Growth Factor- β. Biochem. Biophys. Res. Commun. 1989, 158 (3), 1060– 1065,  DOI: 10.1016/0006-291X(89)92829-5

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    Brown, M. L.; Schneyer, A. L. Emerging Roles for the TGFβ Family in Pancreatic β-Cell Homeostasis. Trends Endocrinol. Metab. 2010, 21 (7), 441– 448,  DOI: 10.1016/j.tem.2010.02.008

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    Emerging roles for the TGFβ family in pancreatic β-cell homeostasis

    Brown, Melissa L.; Schneyer, Alan L.

    Trends in Endocrinology and Metabolism (2010), 21 (7), 441-448CODEN: TENME4; ISSN:1043-2760. (Elsevier Ltd.)

    A review. Loss of functional β-cells is the primary cause of type 2 diabetes, so that there is an acute need to understand how β-cell no. and function are regulated in the adult under normal physiol. conditions. Recent studies suggest that members of the transforming growth factor (TGF)-β family regulate β-cell function and glucose homeostasis. These factors are also likely to influence β-cell proliferation and(or) the incorporation of new β-cells from progenitors in adults. Sol. TGFβ antagonists also appear to have important roles in maintaining homeostasis, and the coordinated activity of TGFβ family members is likely to regulate the differentiation and function of adult β-cells, raising the possibility of developing new diabetes therapies based on TGFβ agonists or antagonists.
54. 54

    Grewal, I. S.; Grewal, K. D.; Wong, F. S.; Wang, H.; Picarella, D. E.; Janeway, C. A.; Flavell, R. A. Expression of Transgene Encoded TGF-β in Islets Prevents Autoimmune Diabetes in NOD Mice by a Local Mechanism. J. Autoimmun. 2002, 19 (1–2), 9– 22,  DOI: 10.1006/jaut.2002.0599

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    Moritani, M.; Yamasaki, S.; Kagami, M.; Suzuki, T.; Yamaoka, T.; Sano, T.; Hata, J. I.; Itakura, M. Hypoplasia of Endocrine and Exocrine Pancreas in Homozygous Transgenic TGF-B1. Mol. Cell. Endocrinol. 2005, 229 (1–2), 175– 184,  DOI: 10.1016/j.mce.2004.08.007

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    Negi, C. K.; Bajard, L.; Kohoutek, J.; Blaha, L. An Adverse Outcome Pathway Based in Vitro Characterization of Novel Flame Retardants-Induced Hepatic Steatosis. Environ. Pollut. 2021, 289, 117855  DOI: 10.1016/j.envpol.2021.117855

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    An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis

    Negi, Chander K.; Bajard, Lola; Kohoutek, Jiri; Blaha, Ludek

    Environmental Pollution (Oxford, United Kingdom) (2021), 289 (), 117855CODEN: ENPOEK; ISSN:0269-7491. (Elsevier Ltd.)

    A wide range of novel replacement flame retardants (nFRs) is consistently detected in increasing concns. in the environment and human matrixes. Evidence suggests that nFRs exposure may be assocd. with disruption of the endocrine system, which has been linked with the etiol. of various metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). NAFLD is a multifactorial disease characterized by the uncontrolled accumulation of fats (lipids) in the hepatocytes and involves multiple-hit pathogenesis, including exposure to occupational and environmental chems. such as organophosphate flame retardants (OPFRs). In the present study we aimed to investigate the potential mechanisms of the nFRs-induced hepatic steatosis in the human liver cells. In this study, we employed an in vitro bioassay toolbox to assess the key events (KEs) in the proposed adverse outcome pathways (AOP) (s) for hepatic steatosis. We examd. nine nFRs using AOP- based in vitro assays measuring KEs such as lipid accumulation, mitochondrial dysfunction, gene expression, and in silico approach to identify the putative mol. initiating events (MIEs). Our findings suggest that several tested OPFRs induced lipid accumulation in human liver cell culture. Tricresyl phosphate (TMPP), tri-Ph phosphate (TPHP), tris(1,3-dichloropropyl) phosphate (TDCIPP), and 2-ethylhexyl di-Ph phosphate (EHDPP) induced the highest lipid accumulation by altering the expression of genes encoding hepatic de novo lipogenesis and mitochondrial dysfunction depicted by decreased cellular ATP prodn. Available in vitro data from ToxCast and in silico mol. docking suggests that pregnane X receptor (PXR) and peroxisome proliferator-activated receptor gamma (PPARγ) could be the mol. targets for the tested nFRs. The study identifies several nFRs, such as TMPP and EHDPP, TPHP, and TDCIPP, as potential risk factor for NAFLD and advances our understanding of the mechanisms involved, demonstrating the utility of an AOP-based strategy for screening and prioritizing chems. and elucidating the mol. mechanisms of toxicity.
57. 57

    Hao, Z.; Zhang, Z.; Lu, D.; Ding, B.; Shu, L.; Zhang, Q.; Wang, C. Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells. Chem. Res. Toxicol. 2019, 32 (6), 1250– 1258,  DOI: 10.1021/acs.chemrestox.9b00058

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    57

    Organophosphorus Flame Retardants Impair Intracellular Lipid Metabolic Function in Human Hepatocellular Cells

    Hao, Zhengliang; Zhang, Zhijie; Lu, Dezhao; Ding, Bin; Shu, Lin; Zhang, Quan; Wang, Cui

    Chemical Research in Toxicology (2019), 32 (6), 1250-1258CODEN: CRTOEC; ISSN:0893-228X. (American Chemical Society)

    Organophosphorus flame retardants (OPFRs), a replacement for brominated flame retardants, have gradually been accepted as endocrine disrupting chems. (EDCs). Recently, evidence has shown that these EDCs could cause chronic health problems, such as obesity, and referred to as metabolic disruptors. However, the disturbance to lipid metab. caused by OPFRs remains poorly understood, esp. at biol. mol. levels. Herein, we used the human hepatocellular cells (HepG2) to study the lipid metab. disruption caused by nine OPFRs (halogenated-, aryl-, and alkyl-contg.). All the tested OPFRs, excluding the long carbon chain alkyl-OPFRs, could cause intracellular triglyceride (TG) and/or total cholesterol (TC) accumulation. In detail, aryl-OPFRs (TPhP and TCP) induced both TC and TG deposition. Halogenated-OPFRs (TCEP, TBPP, TDCPP, and TCPP) induced intracellular TG accumulation, and only TDCPP also induced TC accumulation. Furthermore, TPhP induced lipid accumulation through regulation genes encoding proteins involved in fatty acid β-oxidn., lipid, and fatty acid synthesis. All the halogenated-OPFRs cause TG accumulation only, enacted through β-oxidn. rather than lipid synthesis. TPhP and TDCPP induced TC accumulation through both PPARγ and srebp2 signaling. Mitochondrial dysfunction including decreased oxygen consumption rate and ATP content may also contribute to lipid metabolic disruption by the tested OPFRs. Our data indicated that halogenated- and aryl-OPFRs may not be safe candidates, and further information should be made available as potential for, as well as the mechanism of, metabolic disruption. And long carbon chain alkyl-OPFRs may be safer than the other two groups.
58. 58

    An, J.; Jiang, J.; Tang, W.; Zhong, Y.; Ren, G.; Shang, Y.; Yu, Z. Lipid Metabolic Disturbance Induced by Triphenyl Phosphate and Hydroxy Metabolite in HepG2 Cells. Ecotoxicol. Environ. Saf. 2023, 262, 115160,  DOI: 10.1016/j.ecoenv.2023.115160

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59. 59

    Du, Z.; Zhang, Y.; Wang, G.; Peng, J.; Wang, Z.; Gao, S. TPhP Exposure Disturbs Carbohydrate Metabolism, Lipid Metabolism, and the DNA Damage Repair System in Zebrafish Liver. Sci. Rep. 2016, 6 (1), 1– 10,  DOI: 10.1038/srep21827

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    Zhang, Q.; Zheng, S.; Shi, X.; Luo, C.; Huang, W.; Lin, H.; Peng, J.; Tan, W.; Wu, K. Neurodevelopmental Toxicity of Organophosphate Flame Retardant Triphenyl Phosphate (TPhP) on Zebrafish (Danio Rerio) at Different Life Stages. Environ. Int. 2023, 172, 107745  DOI: 10.1016/j.envint.2023.107745

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61. 61

    Zhang, Y. T.; Chen, R.; Wang, F.; Huang, Z.; He, S.; Chen, J.; Mu, J. Potential Involvement of the Microbiota-Gut-Brain Axis in the Neurotoxicity of Triphenyl Phosphate (TPhP) in the Marine Medaka (Oryzias Melastigma) Larvae. Sci. Total Environ. 2022, 817, 152945  DOI: 10.1016/j.scitotenv.2022.152945

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    Hong, X.; Chen, R.; Hou, R.; Yuan, L.; Zha, J. Triphenyl Phosphate (TPHP)-Induced Neurotoxicity in Adult Male Chinese Rare Minnows (Gobiocypris Rarus). Environ. Sci. Technol. 2018, 52 (20), 11895– 11903,  DOI: 10.1021/acs.est.8b04079

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    62

    Triphenyl Phosphate (TPHP)-Induced Neurotoxicity in Adult Male Chinese Rare Minnows (Gobiocypris rarus)

    Hong, Xiangsheng; Chen, Rui; Hou, Rui; Yuan, Lilai; Zha, Jinmiao

    Environmental Science & Technology (2018), 52 (20), 11895-11903CODEN: ESTHAG; ISSN:0013-936X. (American Chemical Society)

    The neurotoxicity of tri-Ph phosphate (TPHP) in exposed humans and lab. animals is under debate. The rapid crossing of the blood-brain barrier (BBB) and high distribution of TPHP in fish brains have raised widespread concerns about potential neurotoxicity. Adult male Chinese rare minnows (Gobiocypris rarus) were used as a model and exposed to 0, 20, or 100 μg/L TPHP for 28 days. We evaluated the BBB permeability, neuroinflammatory response, cell proliferation and apoptosis, synaptic plasticity and synapse loss in fish brains via the learning/memory performance of fish following 28 days of TPHP exposure. TPHP significantly increased the BBB permeability, activated the neuroinflammatory response, and decreased the tight junction-related mRNA levels of claudin-5α and occludin in the fish brain. In addn., cell proliferation was inhibited by treatment with 100 μg/L TPHP, but no significant apoptosis was obsd. in the brain. Fish exposed to 100 μg/L TPHP exhibited significantly decreased dendritic arborization in pyramidal neurons in the cerebellum (Ce), and the maze test indicated impaired learning/memory performance. Taken together, these findings provide scientific evidence that TPHP is neurotoxic to fish and further suggest that TPHP may not a safe alternative for aquatic organisms.
63. 63

    Shi, Q.; Wang, M.; Shi, F.; Yang, L.; Guo, Y.; Feng, C.; Liu, J.; Zhou, B. Developmental Neurotoxicity of Triphenyl Phosphate in Zebrafish Larvae. Aquat. Toxicol. 2018, 203, 80– 87,  DOI: 10.1016/j.aquatox.2018.08.001

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    Developmental neurotoxicity of triphenyl phosphate in zebrafish larvae

    Shi, Qipeng; Wang, Min; Shi, Fengqiong; Yang, Lihua; Guo, Yongyong; Feng, Chenglian; Liu, Jingfu; Zhou, Bingsheng

    Aquatic Toxicology (2018), 203 (), 80-87CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)

    Tri-Ph phosphate (TPhP), a typical organophosphate ester, is frequently detected in the environment and biota samples. It has been implicated as a neurotoxin as its structure is similar to neurotoxic organophosphate pesticides. The purpose of the present study was to investigate its potential developmental neurotoxicity in fish by using zebrafish larvae as a model. Zebrafish (Danio rerio) embryos were exposed to 0.8, 4, 20 and 100μg/L of TPhP from 2 until 144 h post-fertilization. TPhP was found to have high bioconcns. in zebrafish larvae after exposure. Further, it significantly reduced locomotor activity as well as the heart rate at the 100μg/L concn. TPhP exposure significantly altered the content of the neurotransmitters γ-aminobutyric and histamine. Downregulation of the genes related to central nervous system development (e.g., α1-tubulin, mbp, syn2a, shha, and elavl3) as well as the corresponding proteins (e.g., α1-tubulin, mbp, and syn2a) was obsd., but the gap-43 protein was found to upregulated. Finally, marked inhibition of total acetylcholinesterase activity, which is considered as a biomarker of neurotoxicant exposure, was also obsd. in the larvae. Our results indicate that exposure to environmentally relevant concns. of TPhP can affect different parameters related to center nervous system development, and thus contribute to developmental neurotoxicity in early developing zebrafish larvae.
64. 64

    Zhong, X.; Yu, Y.; Wang, C.; Zhu, Q.; Wu, J.; Ke, W.; Ji, D.; Niu, C.; Yang, X.; Wei, Y. Hippocampal Proteomic Analysis Reveals the Disturbance of Synaptogenesis and Neurotransmission Induced by Developmental Exposure to Organophosphate Flame Retardant Triphenyl Phosphate. J. Hazard. Mater. 2021, 404, 124111  DOI: 10.1016/j.jhazmat.2020.124111

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    64

    Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate

    Zhong, Xiali; Yu, Yuejin; Wang, Can; Zhu, Qicheng; Wu, Jingwei; Ke, Weijian; Ji, Di; Niu, Congying; Yang, Xifei; Wei, Yanhong

    Journal of Hazardous Materials (2021), 404 (Part_B), 124111CODEN: JHMAD9; ISSN:0304-3894. (Elsevier B.V.)

    With the spread of organophosphorus flame retardants (OPFRs), the environmental and health risks they induce are attracting attention. Tri-Ph phosphate (TPHP) is a popular alternative to brominated flame retardant and halogenated OPFRs. Neurodevelopmental toxicity is TPHP's primary adverse effect, whereas the biomarkers and the modes of action have yet to be elucidated. 0.5, 5, And 50 mg/kg of TPHP were orally administered to mice from postnatal day 10 (P10) to P70. The behavioral tests showed a compromised learning and memory capability. Proteomic anal. of the hippocampus exposed to 0.5 or 50 mg/kg of TPHP identified 531 differentially expressed proteins that were mainly involved in axon guidance, synaptic function, neurotransmitter transport, exocytosis, and energy metab. Immunoblot and immunofluorescence anal. showed that exposure to TPHP reduced the protein levels of TUBB3 and SYP in the synapses of hippocampal neurons. TPHP exposure also downregulated the gene expression of neurotransmitter receptors including Grins, Htr1α, and Adra1α in a dose-dependent fashion. Moreover, the calcium-dependent synaptic exocytosis governed by synaptic vesicle proteins STX1A and SYT1 was inhibited in the TPHP-treated hippocampus. The authors' results reveal that TPHP exposure causes abnormal learning and memory behaviors by disturbing synaptogenesis and neurotransmission.
65. 65

    Zhang, X.; Zhou, Q.; Li, X.; Zou, W.; Hu, X. Integrating Omics and Traditional Analyses to Profile the Synergistic Toxicity of Graphene Oxide and Triphenyl Phosphate. Environ. Pollut. 2020, 263, 114473  DOI: 10.1016/j.envpol.2020.114473

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    Ye, L.; Zhang, X.; Wang, P.; Zhang, Y.; He, S.; Li, Y.; Li, S.; Liang, K.; Liao, S.; Gao, Y.; Zhou, S.; Peng, Q. Low Concentration Triphenyl Phosphate Fuels Proliferation and Migration of Hepatocellular Carcinoma Cells. Environ. Toxicol. 2022, 37 (10), 2445– 2459,  DOI: 10.1002/tox.23609

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    Yue, J.; Sun, X.; Duan, X.; Sun, C.; Chen, H.; Sun, H.; Zhang, L. Triphenyl Phosphate Proved More Potent than Its Metabolite Diphenyl Phosphate in Inducing Hepatic Insulin Resistance through Endoplasmic Reticulum Stress. Environ. Int. 2023, 172, 107749  DOI: 10.1016/j.envint.2023.107749

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    Sanchez, O. F.; Lee, J.; Yu King Hing, N.; Kim, S. E.; Freeman, J. L.; Yuan, C. Lead (Pb) Exposure Reduces Global DNA Methylation Level by Non-Competitive Inhibition and Alteration of Dnmt Expression. Metallomics 2017, 9 (2), 149– 160,  DOI: 10.1039/C6MT00198J

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    Song, C.-X.; He, C. Potential functional roles of DNA demethylation intermediates. Trends Biochem Sci. 2013, 38, 480,  DOI: 10.1016/j.tibs.2013.07.003

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    Potential functional roles of DNA demethylation intermediates

    Song, Chun-Xiao; He, Chuan

    Trends in Biochemical Sciences (2013), 38 (10), 480-484CODEN: TBSCDB; ISSN:0968-0004. (Elsevier Ltd.)

    A review. DNA methylation in the form of 5-methylcytosine (5mC) is a key epigenetic regulator in mammals, and the dynamic balance between methylation and demethylation impacts various processes from development to disease. The recent discovery of the enzymic generation and removal of the oxidized derivs. of 5mC, namely 5-hydroxymethylcysotine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in mammalian cells has led to a paradigm shift in our understanding of the demethylation process. Interestingly, emerging evidence indicates that these DNA demethylation intermediates are dynamic and could themselves carry regulatory functions. Here, we discuss 5hmC, 5fC, and 5caC as new epigenetic DNA modifications that could have distinct regulatory functions in conjunction with potential protein partners.
70. 70

    Takayama, K.; Shimoda, N.; Takanaga, S.; Hozumi, S.; Kikuchi, Y. Expression Patterns of Dnmt3aa, Dnmt3ab, and Dnmt4 during Development and Fin Regeneration in Zebrafish. Gene Expr. Patterns 2014, 14 (2), 105– 110,  DOI: 10.1016/j.gep.2014.01.005

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    Tang, D.; Zheng, S.; Zheng, Z.; Liu, C.; Zhang, J.; Yan, R.; Wu, C.; Zuo, N.; Wu, L.; Xu, H.; Liu, S.; He, Y. Dnmt1 Is Required for the Development of Auditory Organs via Cell Cycle Arrest and Fgf Signalling. Cell Prolif. 2022, 55 (5), e13225,  DOI: 10.1111/cpr.13225

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    Ni, A.; Fang, L.; Xi, M.; Li, J.; Qian, Q.; Wang, Z.; Wang, X.; Wang, H.; Yan, J. Neurotoxic Effects of 2-Ethylhexyl Diphenyl Phosphate Exposure on Zebrafish Larvae: Insight into Inflammation-Driven Changes in Early Motor Behavior. Sci. Total Environ. 2024, 915, 170131  DOI: 10.1016/j.scitotenv.2024.170131

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    Yi, X.; Qin, H.; Li, G.; Kong, R.; Liu, C. Isomer-Specific Cardiotoxicity Induced by Tricresyl Phosphate in Zebrafish Embryos/Larvae. J. Hazard. Mater. 2024, 474, 134753  DOI: 10.1016/j.jhazmat.2024.134753

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74. 74

    Shi, Q.; Tsui, M. M. P.; Hu, C.; Lam, J. C. W.; Zhou, B.; Chen, L. Acute Exposure to Triphenyl Phosphate (TPhP) Disturbs Ocular Development and Muscular Organization in Zebrafish Larvae. Ecotoxicol. Environ. Saf. 2019, 179, 119– 126,  DOI: 10.1016/j.ecoenv.2019.04.056

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    74

    Acute exposure to triphenyl phosphate (TPhP) disturbs ocular development and muscular organization in zebrafish larvae

    Shi, Qipeng; Tsui, Mirabelle M. P.; Hu, Chenyan; Lam, James C. W.; Zhou, Bingsheng; Chen, Lianguo

    Ecotoxicology and Environmental Safety (2019), 179 (), 119-126CODEN: EESADV; ISSN:0147-6513. (Elsevier B.V.)

    Tri-Ph phosphate (TPhP) is an organophosphate flame retardant that is frequently detected in the environments. TPhP exposure is known to cause developmental toxicity. However, the underlying mol. mechanisms remain underestimated. In the present study, zebrafish embryos were acutely exposed to 0, 4 and 100 μg/L TPhP until 144 h post-fertilization. Profiles of differentially expressed proteins were constructed using a shotgun proteomic. With the input of differential proteins, principal component anal. suggested different protein expression profiles for 4 and 100 μg/L TPhP. Gene ontol. and KEGG pathway analyses further found that effects of TPhP at 4 μg/L targeted phagosome and lysosome activity, while 100 μg/L TPhP mainly affected carbohydrate metab., muscular contraction and phagosome. Based on proteomic data, diverse bioassays were employed to ascertain the effects of TPhP on specific proteins and pathways. At gene and protein levels, expressions of crit. visual proteins were significantly changed by TPhP exposure, including retinoschisin 1a, opsins and crystallins, implying the impairment of ocular development and function. TPhP exposure at 100 μg/L also altered the abundances of diverse muscular proteins and disordered the assembly of muscle fibers. Effects of TPhP on visual development and motor activity may be combined to disturb larval swimming behavior. In summary, current results provided mechanistic clues to the developmental toxicities of TPhP. Future works are inspired to broaden the toxicol. knowledge of TPhP based on current proteomic results.
75. 75

    Shi, Q.; Wang, Z.; Chen, L.; Fu, J.; Han, J.; Hu, B.; Zhou, B. Optical Toxicity of Triphenyl Phosphate in Zebrafish Larvae. Aquat. Toxicol. 2019, 210, 139– 147,  DOI: 10.1016/j.aquatox.2019.02.024

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    Optical toxicity of triphenyl phosphate in zebrafish larvae

    Shi, Qipeng; Wang, Zongyi; Chen, Lianguo; Fu, Juanjuan; Han, Jian; Hu, Bing; Zhou, Bingsheng

    Aquatic Toxicology (2019), 210 (), 139-147CODEN: AQTODG; ISSN:0166-445X. (Elsevier B.V.)

    Tri-Ph phosphate (TPhP) has been shown to cause developmental neurotoxicty. Considering the visual system is a sensitive target, in the present study, we investigated the potential toxicity of TPhP on the visual development and function in zebrafish larvae. Embryos were exposed to 0, 0.1, 1, 10, and 30μg/L TPhP from 2 to 144 h post-fertilization (hpf). The transcription of photoreceptor opsin genes, and histopathol. changes in the retina and visual behavior (optokinetic and phototactic responses) were evaluated. TPhP significantly downregulated the transcription of opsin genes (zfrho, opn1sw1, opn1sw2, opn1mw1, opn1mw2, opn1mw3, opn1mw4, opn1lw1 and opn1lw2) in all exposure groups. Histopathol. anal. revealed that the areas of the outer nuclear layer (ONL), inner nuclear layer (INL), and inner plexiform layer (IPL) of the retina were significantly reduced in the 10 and 30μg/L TPhP groups. The no. of ganglion cells was reduced significantly in the 30μg/L group. The optokinetic response (OKR) and phototactic response showed dose-dependent decreases caused by impaired visual function, which was confirmed by unchanged locomotor activity. The results indicated that exposure to environmentally relevant concns. of TPhP could inhibit the transcription of genes related to visual function and impair retinal development, thus leading to visual impairment in zebrafish larvae.
76. 76

    Qi, Z.; Chen, M.; Song, Y.; Wang, X.; Li, B.; Chen, Z. F.; Tsang, S. Y.; Cai, Z. Acute Exposure to Triphenyl Phosphate Inhibits the Proliferation and Cardiac Differentiation of Mouse Embryonic Stem Cells and Zebrafish Embryos. J. Cell. Physiol. 2019, 234 (11), 21235– 21248,  DOI: 10.1002/jcp.28729

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    76

    Acute exposure to triphenyl phosphate inhibits the proliferation and cardiac differentiation of mouse embryonic stem cells and zebrafish embryos

    Qi, Zenghua; Chen, Min; Song, Yuanyuan; Wang, Xiya; Li, Bingkun; Chen, Zhi-Feng; Tsang, Suk Ying; Cai, Zongwei

    Journal of Cellular Physiology (2019), 234 (11), 21235-21248CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)

    Attention has recently paid to the interaction of tri-Ph phosphate (TPHP) and body tissues, particularly within the reproductive and development systems, due to its endocrine-disrupting properties. However, the acute effects of TPHP on early embryonic development remain unclear. Here, we used mouse embryonic stem cells (mESC) and zebrafish embryos to investigate whether TPHP is an embryo toxicant. First, we found that continuous exposure of TPHP decreased the proliferation and increased the apoptotic populations of mESCs in a concn.-dependent manner. Results of mass spectrometry showed that the intracellular concn. of TPHP reached 39.45 ± 7.72μg/g wt./wt. after 3 h of acute exposure with TPHP (38.35μM) but gradually decreased from 3 h to 48 h. Addnl., DNA damage was detected in mESCs after a short-term treatment with TPHP, which in turn, activated DNA damage responses, leading to cell cycle arrest by changing the expression levels of p53, proliferating cell nuclear antigen, and Y15-phosphorylated Cdk I. Furthermore, our results revealed that short-term treatment with TPHP disturbed cardiac differentiation by decreasing the expression levels of Oct4, Sox2, and Nanog and transiently reduced the glycolysis capacity in mESCs. In zebrafish embryos, exposure to TPHP resulted in broad, concn.-dependent developmental defects and coupled with heart malformation and reduced heart rate. In conclusion, the two models demonstrate that acute exposure to TPHP affects early embryonic development and disturbs the cardiomyogenic differentiation.
77. 77

    Rai, K.; Jafri, I. F.; Chidester, S.; James, S. R.; Karpf, A. R.; Cairns, B. R.; Jones, D. A. Dnmt3 and G9a Cooperate for Tissue-Specific Development in Zebrafish. J. Biol. Chem. 2010, 285 (6), 4110– 4121,  DOI: 10.1074/jbc.M109.073676

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    Germain, L.; Winn, L. M. The Flame Retardant Triphenyl Phosphate Alters the Epigenome of Embryonic Cells in an Aquatic in Vitro Model. J. Appl. Toxicol. 2024, 44 (7), 965– 977,  DOI: 10.1002/jat.4589

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