Ecological geneticsEcological geneticsЭкологическая генетика1811-09322411-9202Eco-Vector1131910.17816/ecogen17387-98Genetic toxicologyГенетическая токсикологияResearch ArticleBisphenol a and human diseases. Mechanisms of actionБисфенол а и болезни человека. Механизмы действияhttps://orcid.org/0000-0002-1643-955857198516110J-8543-20183343-2970DergachevaNatalia I.ДергачеваНаталья Игоревна
Russian Federation

Master of Biology, PhD student, Researcher, Laboratory of Molecular cytogenetics of mammalian development, Department of Molecular genetics

Магистр биологии, аспирант, научный сотрудник, лаборатория молекулярной цитогенетики развития млекопитающих, отдел молекулярной генетики

natalia-9999@mail.ruhttps://orcid.org/0000-0002-6292-41677003713993J-7779-20134929-4630PatkinEugene L.ПаткинЕвгений Львович
Russian Federation

DSc, PhD, Prof., Head of Laboratory of Molecular cytogenetics of mammalian development, Department of Molecular genetics

доктор биологических наук, профессор, заведующий Лабораторией молекулярной цитогенетики развития млекопитающих, отдел молекулярной генетики

elp44@mail.ruhttps://orcid.org/0000-0003-2127-04596602838276H-4484-20144155-7314SuchkovaIrina O.СучковаИрина Олеговна
Russian Federation

PhD, Senior Researcher, Laboratory of Molecular cytogenetics of mammalian development, Department of Molecular genetics

кандидат биологических наук, старший научный сотрудник, лаборатория молекулярной цитогенетики развития млекопитающих, отдел молекулярной генетики

irsuchkova@mail.ruhttps://orcid.org/0000-0002-8587-13287003953555G-4791-20157334-4881SofronovHenrikh A.СофроновГенрих Александрович
Russian Federation

DSc, PhD, Prof., Academician of RAS, Scientific director of Federal State Budget Scientific Institution «Institute of Experimental Medicine»

доктор медицинских наук, профессор, академик РАН, научный руководитель Федерального государственного бюджетного научного учреждения «Институт экспериментальной медицины»

gasofronov@mail.ruFederal State Budget Scientific Institution «Institute of Experimental Medicine»Федеральное государственное бюджетное научное учреждение «Институт экспериментальной медицины»300420191509201917387980503201930042019Copyright ©; 2019, Dergacheva N.I., Patkin E.L., Suchkova I.O., Sofronov H.A.Copyright ©; 2019, Дергачева Н.И., Паткин Е.Л., Сучкова И.О., Софронов Г.А.2019Dergacheva N.I., Patkin E.L., Suchkova I.O., Sofronov H.A.Дергачева Н.И., Паткин Е.Л., Сучкова И.О., Софронов Г.А.http://creativecommons.org/licenses/by/4.0https://journals.eco-vector.com/ecolgenet/article/view/11319

The review describes the molecular mechanisms and biological effects of bisphenol A exposure, which is a chemical (ecotoxicant) that destroys the endocrine system and has epigenetic toxicity.

В обзоре рассматриваются молекулярные механизмы и биологические эффекты воздействия экотоксиканта бисфенола А, который относится к химическим веществам, разрушающим эндокринную систему, и обладает эпигенетической токсичностью.

xenoestrogensepigenetic modificationsepimutationgene expressioncongenital abnormalitieschronic diseasescancerontogenesisксеноэстрогеныэпигенетические модификацииэпимутацииэкспрессия геновврожденные патологиихронические болезнираконтогенезRussian Foundation for Basic ResearchРоссийский фонд фундаментальных исследованийWHO/UNEP. State of the science of endocrine disrupting chemicals-2012. WHO: Geneva; 2013. Available at: http://www.who.int/ceh/publications/endocrine/en/index.html.Yoon K, Kwack SJ, Kim HS, Lee B-M. Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases. J Toxicol Environ Health B Crit Rev. 2014;17(3):127-174. https://doi.org/10. 1080/10937404. 2014. 882194.Aubert N, Ameller T, Legrand J-J. Systemic exposure to parabens: pharmacokinetics, tissue distribution, excretion balance and plasma metabolites of [14C]-methyl-, propyl- and butylparaben in rats after oral, topical or subcutaneous administration. Food Chem Toxicol. 2012;50(3-4): 445-454. https://doi.org/10. 1016/j.fct.2011. 12. 045.Peña CJ, Monk C, Champagne FA. Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS ONE. 2012;7(6): e39791. https://doi.org/10. 1371/journal.pone.0039791.Xin F, Susiarjo M, Bartolomei MS. Multigenerational and transgenerational effects of endocrine disrupting chemicals: a role for altered epigenetic regulation. Semin Cell Dev Biol. 2015;43:66-75. https://doi.org/10. 1016/j.semcdb.2015. 05. 008.Ideta-Otsuka M, Igarashi K, Narita M, Hirabayashi Y. Epigenetic toxicity of environmental chemicals upon exposure during development – bisphenol A and valproic acid may have epigenetic effects. Food Chem Toxicol. 2017;109(1):812-816. https://doi.org/10. 1016/j.fct.2017. 09. 014.Софронов Г.А., Паткин Е.Л. Эпигенетическая токсикология: перспективы развития // Токсикологический вестник. – 2018. – № 1. – С. 2–7. [Sofronov GA, Patkin EL. Epegentic toxicology: perspectives of the development. Toxicological Review. 2018;(1):2-7. (In Russ.)]Marczylo EL, Jacobs MN, Gant TW. Environmentally induced epigenetic toxicity: potential public health concerns. Crit Rev Toxicol. 2016;46(8):676-700. https://doi.org/10. 1080/10408444. 2016. 1175417.Vandenberg LN, Maffini MV, Sonnenschein C, et al. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr Rev. 2009;30(1): 75-95. https://doi.org/10. 1210/er.2008-0021.Geens T, Goeyens L, Covaci A. Are potential sources for human exposure to bisphenol-A overlooked? Int J Hyg Environ Health. 2011;214(5):339-347. https://doi.org/10. 1016/j.ijheh.2011. 04. 005.Geens T, Aerts D, Berthot C, et al. A review of dietary and non-dietary exposure to bisphenol-A. Food Chem Toxicol. 2012; 50(10):3725-3740. https://doi.org/10. 1016/j.fct.2012. 07. 059.Cooper JE, Kendig EL, Belcher SM. Assessment of bisphenol A released from reusable plastic, aluminium and stainless steel water bottles. Chemosphere. 2011;85(6):943-7. https://doi.org/10. 1016/j.chemosphere.2011. 06. 060.Cao X-L, Corriveau J, Popovic S. Bisphenol A in canned food products from Canadian markets. J Food Prot. 2010;73(6):1085-1089. https://doi.org/10. 4315/0362-028X-73. 6. 1085.Biedermann S, Tschudin P, Grob K. Transfer of bisphenol A from thermal printer paper to the skin. Anal Bioanal Chem. 2010; 398(1):571-576. https://doi.org/10. 1007/s00216-010-3936-9.Паткин Е.Л., Павлинова Л.И., Софронов Г.А. Влияние экотоксикантов на эмбриогенез и гаметогенез млекопитающих: эпигенетические механизмы // Биосфера. – 2013. – T. 5. – № 4. – С. 450–472. [Patkin EL, Pavlinova LI, Sofronov GA. Vliyanie ekotoksikantov na embriogenez i gametogenez mlekopitayushchikh: epigeneticheskie mekhanizmy. Biosfera. 2013;5(4): 450-472. (In Russ.)]Kundakovic M, Gudsnuk K, Franks B, et al. Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proc Natl Acad Sci USA. 2013;110(24):9956-9961. https://doi.org/10. 1073/pnas.1214056110.Rezg R, El-Fazaa S, Gharbi N, Mornagui B. Bisphenol A and human chronic diseases: current evidences, possible mechanisms, and future perspectives. Environ Int. 2014; 64:83-90. https://doi.org/10. 1016/j.envint.2013. 12. 007.Huang B, Jiang C, Luo J, et al. Maternal exposure to bisphenol A may increase the risks of Parkinsons disease through down-regulation of fetal IGF-1 expression. Med Hypotheses. 2014;82(3):245-249. https://doi.org/10. 1016/j.mehy.2013. 10. 023.Alonso-Magdalena P, Ropero AB, Soriano S, et al. Bisphenol-A: a new diabetogenic factor? Hormones (Athens). 2010;9(2):118-26. https://doi.org/10. 1007/bf03401277.Alonso-Magdalena P, Quesada I, Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nat Rev Endocrinol. 2011;7(6):346-353. https://doi.org/10. 1038/nrendo.2011. 56.Moon MK, Kim MJ, Jung IK, et al. Bisphenol A impairs mitochondrial function in the liver at doses below the no observed adverse effect level. J Korean Med Sci. 2012;27(6):644-652. https://doi.org/10. 3346/jkms.2012. 27. 6. 644.Donohue KM, Miller RL, Perzanowski MS, et al. Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children. J Allergy Clin Immunol. 2013;131(3):736-742. https://doi.org/10. 1016/j.jaci.2012. 12. 1573.Spanier AJ, Kahn RS, Kunselman AR, et al. Prenatal exposure to bisphenol A and child wheeze from birth to 3 years of age. Environ Health Perspect. 2012;120(6): 916-920. https://doi.org/10. 1289/ehp.1104175.Baccarelli A, Ghosh S. Environmental exposures, epigenetics and vascular disease. Curr Opi Clin Nutr Metab Care. 2012;15(4):323-329. https://doi.org/10. 1097/MCO.0b013e328354bf5c.Melzer D, Gates P, Osborne NJ, et al. Urinary bisphenol A concentration and angiography-defined coronary artery stenosis. PLoS One. 2012;7(8):e43378. https://doi.org/10. 1371/journal.pone.0043378.Baccarelli A, Cassano PA, Litonjua A, et al. Cardiac autonomic dysfunction: effects from particulate air pollution and protection by dietary methyl nutrients and metabolic polymorphisms. Circulation. 2008;117(14):1802-1809. https://doi.org/10. 1161/CIRCULATIONAHA.107. 726067.Ahmed RG, Walaa GH, Asmaa FS. Suppressive effects of neonatal bisphenol A on the neuroendocrine system. Toxicol Ind Health. 2018;34(6):397-407. https://doi.org/10. 1177/0748233718757082.Kawai K, Nozaki T, Nishikata H, et al. Aggressive behavior and serum testosterone concentration during the maturation process of male mice: the effects of fetal exposure to bisphenol A. Environ Health Perspect. 2003;111(2): 175-178. https://doi.org/10. 1289/ehp.5440.Richter CA, Birnbaum LS, Farabollini F, et al. In vivo effects of bisphenol A in laboratory rodent studies. Reprod Toxicol. 2007;24(2):199-224. https://doi.org/10. 1016/j.reprotox.2007. 06. 004.Itoh K, Yaoi T, Fushiki S. Bisphenol A, an endocrine-disrupting chemical, and brain development. Neuropathology. 2012;32(4):447-457. https://doi.org/10. 1111/j.1440-1789. 2011. 01287. x.Kim K, Son TG, Park HR, et al. Potencies of bisphenol A on the neuronal differentiation and hippocampal neurogenesis. J Toxicol Environ Health A. 2009;72(21-22): 1343-51. https://doi.org/10. 1080/15287390903212501.Iwakura T, Iwafuchi M, Muraoka D, et al. In vitro effects of bisphenol A on developing hypothalamic neurons. Toxicology. 2010;272(1-3):52-58. https://doi.org/10. 1016/j.tox.2010. 04. 005Brown JS Jr. Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia. Schizophr Bull. 2009;35(1):256-278. https://doi.org/10. 1093/schbul/sbm147.Jain S, Kumar CH, Suranagi UD, Mediratta PK. Protective effect of N-acetylcysteine on bisphenol A-induced cognitive dysfunction and oxidative stress in rats. Food Chem Toxicol. 2011;49(6):1404-1409. https://doi.org/10. 1016/j.fct.2011. 03. 032.Mok-Lin E, Ehrlich S, Williams PL, et al. Urinary bisphenol A concentrations and ovarian response among women undergoing IVF. Int J Androl. 2010;33(2):385-393. https://doi.org/10. 1111/j.1365-2605. 2009. 01014. x.Jasarevic E, Sieli PT, Twellman EE, et al. Disruption of adult expression of sexually selected traits by developmental exposure to bisphenol A. Proc Natl Acad Sci USA. 2011;108(28):11715-11720. https://doi.org/10. 1073/pnas.1107958108.Peretz J, Vrooman, L, Ricke WA, et al. Bisphenol A and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect. 2014; 122(8):775-86. https://doi.org/10. 1289/ehp.1307728.Mínguez-Alarcón L, Hauser R, Gaskins AJ. Effects of bisphenol A on male and couple reproductive health: a review. Fertil Steril. 2016;106(4):864-870. https://doi.org/10. 1016/j.fertnstert.2016. 07. 1118.Ikezuki Y, Tsutsumi O, Takai Y, et al. Determination of bisphenol A concentrations in human biological fluids reveals significant early prenatal exposure. Hum Reprod. 2002;17(11):2839-2841. https://doi.org/10. 1093/humrep/17. 11. 2839.Balakrishnan B, Henare K, Thorstensen EB, et al. Transfer of bisphenol A across the human placenta. Am J Obstet Gynecol. 2010; 202(4):393: e1-7. https://doi.org/10. 1016/j.ajog.2010. 01. 025.Guida M, Troisi J, Ciccone C, et al. Bisphenol A and congenital developmental defects in humans. Mutat Res. 2015;774:33-39. https://doi.org/10. 1016/j.mrfmmm.2015. 02. 007.Miao M, YuanW, He Y, et al. In utero exposure to bisphenol-A and anogenital distance of male offspring. Birth Defects Res A Clin Mol Teratol. 2011;91(10):867-872. https://doi.org/10. 1002/bdra.22845.Chou WC, Chen JL, Lin CF, et al. Biomonitoring of bisphenol A concentrations in maternal and umbilical cord blood in regard to birth outcomes and adipokine expression: a birth cohort study in Taiwan. Environ Health. 2011; 10(1):94. https://doi.org/10. 1186/1476-069X-10-94.Welshons WV, Nagel SC, vom Saal FS. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006;147(6):56-69. https://doi.org/10. 1210/en.2005-1159.Murray TJ, Maffini MV, Ucci AA, et al. Induction of mammary gland ductal hyperplasias and carcinoma in situ following fetal bisphenol A exposure. Reprod Toxicol. 2007;23(3):383-390. https://doi.org/10. 1016/j.reprotox.2006. 10. 002.Wang J, Jenkins S, Lamartiniere CA. Cell proliferation and apoptosis in rat mammary glands following combinational exposure to bisphenol A and genistein. BMC Cancer. 2014;14(1):379. https://doi.org/10. 1186/1471-2407-14-379.Weber Lozada K, Keri RA. Bisphenol A increases mammary cancer risk in two distinct mouse models of breast cancer. Biol Reprod. 2011;85(3):490-497. https://doi.org/10. 1095/biolreprod.110. 090431.Leung YK, Govindarajah V, Cheong A, et al. Gestational high-fat diet and bisphenol A exposure heightens mammary cancer risk. Endocr Relat Cancer. 2017;24(7):365-378. https://doi.org/10. 1530/ERC-17-0006.Zhou W, Liu J, Liao L, et al. Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells. Mol Cell Endocrinol. 2008;283(1-2): 12-18. https://doi.org/10. 1016/j.mce.2007. 10. 010.Prins GS, Tang WY, Belmonte J, et al. Developmental exposure to bisphenol A increases prostate cancer susceptibility in adult rats: epigenetic mode of action is implicated. Fertil Steril. 2008;89(2):е41. https://doi.org/10. 1016/j.fertnstert.2007. 12. 023.De Flora S, Micale RT, La Maestra S, et al. Upregulation of clusterin in prostate and DNA damage in spermatozoa from bisphenol A-treated rats and formation of DNA adducts in cultured human prostatic cells. Toxicol Sci. 2011; 122(1):45-51. https://doi.org/10. 1093/toxsci/kfr096.Gao H, Yang BJ, Li N, et al. Bisphenol A and hormone-associated cancers: current progress and perspectives. Medicine (Baltimore). 2015;94(1):e211. https://doi.org/10. 1097/MD.0000000000000211.Паткин Е.Л., Софронов Г.А. Экологозависимые заболевания человека. Эпигенетические механизмы возникновения и наследования // Медицинский академический журнал. – 2015. – T. 15. – № 3. – С. 7–23. [Patkin EL, Sofronov GA. Environment-dependent human diseases: the epigenetic mechanisms of their development and inheritance. Meditsinskii akademicheskii zhurnal. 2015;15(3):7-23. (In Russ.)]Acconcia F, Pallottini V, Marino M. Molecular mechanisms of action of BPA. Dose-Response. 2015;13(4):1559325815610582. https://doi.org/ 10. 1177/1559325815610582.Kochmanski J, Marchlewicz EH, Dolinoy DC. Longitudinal effects of developmental bisphenol A, variable diet, and physical activity on age-related methylation in blood. Environ Epigenet. 2018;4(3):dvy017. https://doi.org/10. 1093/eep/dvy017.George O, Bryant BK, Chinnasamy R, et al. Bisphenol A directly targets tubulin to disrupt spindle organization in embryonic and somatic cells. ACS Chem Biol. 2008;3(3):167-179. https://doi.org/10. 1021/cb700210u.Takahashi S, Chi XJ, Yamaguchi Y, et al. Mutagenicity of bisphenol A and its suppression by interferon-alpha in human RSa cells. Mutat Res. 2001;490(2):199-207. https://doi.org/10. 1016/S1383-5718(00)00161-3.McGlinchey AJ. The effects of bisphenol A on in-vitro cell viability of mammalian cell line by neutral red assay. The Plymouth Student Scientist. 2009;2(1):25-31.Havranek T, Macho L, Fickova M. Bisphenol-A modulates proliferation of human breast adenocarcinoma cells (MCF-7) by modulating apoptosis and cyclin-A. Endocrine Abstracts. 2013;32:502. https://doi.org/10. 1530/endoabs.32. P502.Yin R, Gu L, Li M, et al. Gene expression profiling analysis of bisphenol A-induced perturbation in biological processes in ER-negative HEK293 cells. PLoS One. 2014;9(6): e98635. https://doi.org/10. 1371/journal.pone.0098635.Yin L, Dai Y, Jiang X, et al. Role of DNA methylation in bisphenol A exposed mouse spermatocyte. Environ Toxicol Pharmacol. 2016;48:265-271. https://doi.org/10. 1016/j.etap.2016. 11. 003.Izzotti A, Kanitz S, D’Agostini F, et al. Formation of adducts by bisphenol A, an endocrine disruptor, in DNA in vitro and in liver and mammary tissue of mice. Mutat Res. 2009;679(1-2):28-32. https://doi.org/10. 1016/j.mrgentox.2009. 07. 011.Minamiyama Y, Ichikawa H, Takemura S, et al. Generation of reactive oxygen species in sperms of rats as an earlier marker for evaluating the toxicity of endocrine-disrupting chemicals. Free Radic Res. 2010;44(12):1398-1406. https://doi.org/10. 3109/10715762. 2010. 510523.Masuyama H, Hiramatsu Y. Involvement of suppressor for Gal1 in the ubiquitin/proteasome-mediated degradation of estrogen receptors. J Biol Chem. 2004;279(13):12020-12026. https://doi.org/10. 1074/jbc.M312762200.Letcher RJ, Sanderson JT, Bokkers A, et al. Effects of bisphenol A-related diphenylalkanes on vitellogenin production in male carp (Cyprinus carpio) hepatocytes and aromatase (CYP19) activity in human H295R adrenocortical carcinoma cells. Toxicol Appl Pharmacol. 2005;209(2): 95-104. https://doi.org/10. 1016/j.taap.2005. 03. 013.Xu BL, Zhao QZ, Gao XY, Hou GJ. Effect of estradiol and bisphenol A on human hepatoblastoma cell viability and telomerase activity. Braz J Med Biol Res. 2015;48(11):1004-1009. https://doi.org/10. 1590/1414-431X20154400.Somogyi V, Horváth TL, Tóth I, et al. Bisphenol A influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture. Acta Vet Hung. 2016;64(4):497-513. https://doi.org/10. 1556/004. 2016. 046.Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J Steroid Biochem Mol Biol. 2006;102(1-5):175-179. https://doi.org/10. 1016/j.jsbmb.2006. 09. 017.Jones DC, Miller GW. The effects of environmental neurotoxicants on the dopaminergic system: a possible role in drug addiction. Biochem Pharmacol. 2008;76(5): 569-581. https://doi.org/10. 1016/j.bcp.2008. 05. 010.Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011;127(1-2):27-34. https://doi.org/10. 1016/j.jsbmb.2011. 05. 002.Wetherill YB, Akingbemi BT, Kanno J, et al. In vitro molecular mechanisms of bisphenol A action. Reprod Toxicol. 2007;24(2):178-198. https://doi.org/10. 1016/j.reprotox.2007. 05. 010.Zhu J, Jiang L, Liu Y, et al. MAPK and NF-κB pathways are involved in bisphenol A-induced TNF-α and IL-6 production in BV2 microglial cells. Inflammation. 2015;38(2): 637-648. https://doi.org/10. 1007/s10753-014-9971-5.Wang Q, Cao J, Zhu Q, et al. Inhibition of voltage-gated sodium channels by bisphenol A in mouse dorsal root ganglion neurons. Brain Research. 2011;1378:1-8. https://doi.org/10. 1016/j.brainres.2011. 01. 022.Soriano S, Ripoll C, Alonso-Magdalena P, et al. Effects of bisphenol A on ion channels: experimental evidence and molecular mechanisms. Steroids. 2016;111:12-20. https://doi.org/10. 1016/j.steroids.2016. 02. 020.Metivier R, Gallais R, Tiffoche C, et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature. 2008;452(7183):45-50. https://doi.org/10. 1038/nature06544.Biddie SC. Chromatin architecture and the regulation of nuclear receptor inducible transcription. J Neuroendocrinol. 2011;23(1):94-106. https://doi.org/10. 1111/j.1365-2826. 2010. 02079. x.Patkin EL, Grudinina NA, Sasina LK, et al. Asymmetric DNA methylation between sister chromatids of metaphase chromosomes in mouse embryos upon bisphenol A action. Reprod Toxicol. 2017;74:1-9. https://doi.org/10. 1016/j.reprotox.2017. 08. 017.Нониашвили Е.М., Грудинина Н.А., Кустова М.Е., и др. Метилирование ДНК в раннем эмбриогенезе мышей под влиянием бисфенола А // Экологическая генетика. – 2017. – Т. 15. – № 3. – С. 42–53. [Noniashvili EM, Grudinina NA, Kustova ME, et al. DNA methylation in early mice embryogenesis under the influence of bisphenol A. Ecological genetics. 2017;15(3):42-53. (In Russ.)]. https://doi.org/10. 17816/ecogen15342-53.Сучкова И.О., Нониашвили Е.М., Дергачева Н.И., и др. Влияние бисфенола А на уровень полногеномного метилирования ДНК в разных частях тела мыши на 12-й день эмбрионального развития // Региональная экология. – 2018. – Т. 53. – № 3. – С. 96–110. [Suchkova IO, Noniashvili EM, Dergacheva NI, et al. Influence of bisphenol A on genome-wide DNA methylation level in different sections of a mouse body on the 12th day of embryonic development. Regional Ecology. 2018;53(3):96-110. (In Russ.)]. https://doi.org/10. 30694/1026-5600-2018-3-96-110.Liu L, Li Y, Tollefsbol TO. Gene-environment interactions and epigenetic basis of human diseases. Curr Issues Mol Biol. 2008;10(1-2):25-36. https://doi.org/10. 21775/cimb.010. 025.Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res. 2011;21(3):381-395. https://doi.org/10. 1038/cr.2011. 22.Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861-74. https://doi.org/10. 1038/nrg3074.Schübeler D. Function and information content of DNA methylation. Nature. 2015;517(7534):321-326. https://doi.org/10. 1038/nature14192.Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057-1068. https://doi.org/10. 1038/nbt.1685.Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 2002;132(8 Suppl):2393S-2400S. https://doi.org/10. 1093/jn/132. 8. 2393S.Rosenfeld CS. Animal models to study environmental epigenetics. Biol Reprod. 2010;82(3):473-488. https://doi.org/10. 1095/biolreprod.109. 080952.Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007;104(32):13056-13061. https://doi.org/10. 1073/pnas.0703739104.Chao HH. Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochem Cell Biol. 2012;137(2):249-259. https://doi.org/10. 1007/s00418-011-0894-z.Laing LV, Viana J, Dempster EL, et al. Bisphenol A causes reproductive toxicity, decreases Dnmt1 transcription, and reduces global DNA methylation in breeding zebrafish (Danio rerio). Epigenetics. 2016;11(7):526-38. https://doi.org/10. 1080/15592294. 2016. 1182272.Miao M, Zhou X, Li Y, et al. LINE-1 hypomethylation in spermatozoa is associated with bisphenol A exposure. Andrology. 2014;2(1):138-144. https://doi.org/10. 1111/j.2047-2927. 2013. 00166. x.Yeo M, Berglund K, Hanna M, et al. Bisphenol A delays the perinatal chloride shift in cortical neurons by epigenetic effects on the Kcc2 promoter. Proc Natl Acad Sci USA. 2013;110(11):4315-4320. https://doi.org/10. 1073/pnas.1300959110.Wang ZY, Lu J, Zhang YZ, et al. Effect of bisphenol A on invasion ability of human trophoblastic cell line BeWo. Int J Clin Exp Pathol. 2015;8(11):14355-64.Ke ZH, Pan JX, Jin LY, et al. Bisphenol A exposure may induce hepatic lipid accumulation via reprogramming the DNA methylation patterns of genes involved in lipid metabolism. Sci Rep. 2016;6(1):31331. https://doi.org/10. 1038/srep31331.Singh S, Li SS. Epigenetic effects of environmental chemicals bisphenol A and phthalates. Int J Mol Sci. 2012;13(8):10143-10153. https://doi.org/10. 3390/ijms130810143.Doshi T, Mehta SS, Dighe V, et al. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology. 2011;289(2-3):74-82. https://doi.org/10. 1016/j.tox.2011. 07. 011.Weng YI, Hsu PY, Liyanarachchi S, et al. Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010;248(2):111-121. https://doi.org/10. 1016/j.taap.2010. 07. 014.Doherty LF, Bromer JG, Zhou Y, et al. In utero exposure to diethylstilbestrol (DES) or bisphenol-A increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer. 2010;1(3):146-155. https://doi.org/10. 1007/s12672-010-0015-9.Ayyanan A, Laribi O, Schuepbach-Mallepell S, et al. Perinatal exposure to bisphenol A increases adult mammary gland progesterone response and cell number. Mol Endocrinol. 2011;25(11):1915-1923. https://doi.org/10. 1210/me.2011-1129.Warita K, Mitsuhashi T, Ohta K, et al. Gene expression of epigenetic regulatory factors related to primary silencing mechanismis less susceptible to lower doses of bisphenol A in embryonic hypothalamic cells. J Toxicol Sci. 2013;38(2):285-289. https://doi.org/10. 2131/jts.38. 285.Kitraki E, Nalvarte I, Alavian-Ghavanini A, Rüegg J. Developmental exposure to bisphenol A alters expression and DNA methylation of Fkbp5, an important regulator of the stress response. Mol Cell Endocrinol. 2015;417:191-199. https://doi.org/10. 1016/j.mce.2015. 09. 028.Huc L, Lemarie A, Gueraud F, Helies-Toussaint C. Low concentrations of bisphenol A induce lipid accumulation mediated by the production of reactive oxygen species in the mitochondria of HepG2 cells. Toxicol in Vitro. 2012;26(5):709-717. https://doi.org/10. 1016/j.tiv.2012. 03. 017.