Journal of Endocrinology and Reproduction

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Alterations in the Epigenetic Landscape Underlying Later-Life Health Effects Due to In-utero Exposure to Endocrine Disrupting Chemicals: A Review of Outcomes from Mice to Men


Affiliations
1 P.G. & Research Department of Advanced Zoology and Biotechnology, Government College for Men, Chennai − 600035, Tamil Nadu, India
2 Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India
     

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Widespread persistence of Endocrine Disrupting Chemicals (EDCs) in the environment has mandated the need to study their potential long-term effects on human health, after acute as well aschronic exposures. The particular focus is on in utero exposure to EDCs in rodent models to look at altered epigenetic programming to result in transgenerational effects in later life of the offspring. This potentially contributes to reproductive and immune dysfunctions, obesity, cancer, and altered brain development and neurobehavioral outcomes. The literature to date establishes the transgenerational effects associated with in utero exposure to EDCs in rodent models. Hence, the aim of this review is to provide a comprehensive overview of epigenetic programming and its regulation in mammals, specially focussing on epigenetic plasticity and susceptibility to exogenous endocrine-active chemicals, EDCs, during the early developmental period, and carried forward to later life using rodent models. The available reports suggest that the key mechanism behind the long-term impact of EDCs is caused by alterations in the epigenetic programming machinery, leading to dysregulated gene expression during adult life. Studies have reported the effect of prenatal exposure to EDCs in the ovarian microRNA expression and function, highlighting ovary as an organ undergoing in utero programming. It ascertains the heightened sensitivity of the organ to exogenous hormone-active compounds, particularly during early development. In addition to this, another key aspect in this review is increased susceptibility of the brain when exposed to even minute quantities of EDCs during embryonic development, resulting in profound alterations in the structural organization of the brain and neurobehavior. Detailed analyses of variables such as folic acid and phytoestrogen content in maternal diet need to be considered as crucial factors while designing experiments and therapeutic interventions. Apart from this, appropriate animal handling during the experimental procedures to eliminate stress in animal models to ensure unbiased results is recommended.

Keywords

Adult Health, Endocrine Disrupting Chemicals (EDCs), Epigenetic Programming, Intrauterine Exposure.
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  • Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, et al. Endocrine-disrupting chemicals: An Endocrine Society scientific statement. Endocrine Reviews. 2009; 30(4):293-342. https://doi.org/10.1210/ er.2009-0002. PMid:19502515 PMCid:PMC2726844.

  • Shanle EK and Xu W. Endocrine disrupting chemicals targeting estrogen receptor signaling: identification and mechanisms of action. Chemical Research in Toxicology. 2010; 24(1):6-19. https://doi.org/10.1021/tx100231n. PMid:21053929 PMCid:PMC3119362.

  • Jones PL, Veenstra GCJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genetics. 1998; 19(2):187-91. https://doi.org/10.1038/561. PMid:9620779.

  • Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. The Journal of Nutrition. 2002; 132(8):2393S-2400S. https://doi.org/10.1093/jn/132.8.2393S. PMid:12163699.

  • Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology. 2003; 23(15):5293-5300. https://doi.org/10.1128/MCB.23.15.5293-5300.2003. PMid:12861015 PMCid:PMC165709.

  • Burdge G, Slater-Jefferies J, Torrens C, et al. Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. British Journal of Nutrition. 2007; 97(03):435. https://doi.org/10.1017/S0007114507352392. PMid:17313703 PMCid:PMC2211514.

  • Anderson OS, Kim JH, Peterson KE, et al. Novel Epigenetic Biomarkers Mediating Bisphenol A Exposure and Metabolic Phenotypes in Female Mice. Endocrinology. 2016; 158(1):31-40. https://doi.org/10.1210/en.2016-1441. PMid:27824486 PMCid:PMC5412976.

  • AnwayM, Skinner M. Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease. Reproductive BioMedicine Online. 2008; 16(1):23-25. https://doi.org/10.1016/S1472-6483(10)60553-6.

  • Ho SM, Tang WY, De Frausto JB, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Research. 2006; 66(11):5624-5632. https://doi.org/10.1158/0008-5472.CAN-06-0516. PMid:16740699 PMCid:PMC2276876.

  • Weaver IC, Champagne FA, Brown SE, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. Journal of Neuroscience. 2005; 25(47):11045-11054. https://doi.org/10.1523/JNEUROSCI.3652-05.2005. PMid:16306417 PMCid:PMC6725868.

  • Koturbash I, Baker M, Loree J, et al. Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo. International Journal of Radiation Oncology, Biology, Physics. 2006; 66(2):327-330. https://doi.org/10.1016/j.ijrobp.2006.06.012. PMid:16965987.

  • Morgan HD, Sutherland HG, Martin DI, Whitelaw E. Epigenetic inheritance at the agouti locus in the mouse. Nature Genetics. 1999: 23(3):314-318 https://doi.org/10.1038/15490. PMid:10545949.

  • Rakyan VK, Chong S, Champ ME, et al. Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs after maternal and paternal transmission. Proceedings of the National Academy of Sciences. 2003; 100(5):2538-2543. https://doi.org/10.1073/pnas.0436776100. PMid:12601169 PMCid:PMC151376.

  • Bygren LO, Tinghog P, Carstensen J, et al. Change in paternal grandmothers early food supply influenced cardiovascular mortality of the female grandchildren. BMC Genetics. 2014; 15(1):12. https://doi.org/10.1186/1471-2156-15-12. PMid:24552514 PMCid:PMC3929550.

  • Manikkam M, Haque M, Guerrero-Bosagna C, et al. Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline. PLoS ONE. 2014; 9(7):e102091. https://doi.org/10.1371/journal.pone.0102091. PMid:25057798 PMCid:PMC4109920.

  • Tang WY, Ho SM. Epigenetic reprogramming and imprinting in origins of disease. Reviews in Endocrine and Metabolic Disorders. 2007; 8(2):173-182. https://doi.org/10.1007/s11154-007-9042-4. PMid:17638084 PMCid:PMC4056338.

  • Li S, Washburn KA, Moore R, et al. Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Research. 1997; 57(19):4356-4359. https://doi.org/10.1002/mc.10015.

  • Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308(5727):1466-1469. https://doi.org/10.1126/science.1108190. PMid:15933200.

  • Dolinoy D, Huang D, Jirtle R. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proceedings of the National Academy of Sciences. 104(32):13056-13061. https://doi.org/10.1073/pnas.0703739104. PMid:17670942 PMCid:PMC1941790.

  • Weinhouse C, Bergin I, Harris C, Dolino, D. Stat3 is A candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health. Epigenetics. 2015; 10(12):1099-1110. https://doi.org/10.1080/15592294.2015. 1107694. PMid:26542749 PMCid:PMC4844208.

  • Barker DJ,. The origins of the developmental origins theory. Journal of Internal Medicine. 2007; 261(5):412- 417. https://doi.org/10.1111/j.1365-2796.2007.01809.x. PMid:17444880.

  • Roseboom T, de Rooij S., Painter R. The Dutch famine and its long-term consequences for adult health. Early Human Development. 2006; 82(8):485-491. https://doi.org/10.1016/j.earlhumdev.2006.07.001. PMid:16876341.

  • Hoek H, Brown A, Susser E. The Dutch Famine and schizophrenia spectrum disorders. Social Psychiatry and Psychiatric Epidemiology. 1998; 33(8):373-379. https://doi. org/10.1007/s001270050068. PMid:9708024.

  • Bhan Khanna S, Dash K, Dwivedee K..Fetal Origin of Adult Disease. JK Science. 2007; 9(4):206-210. https://doi.org/10.1016/j.cppeds.2011.01.001.

  • Bygren LO, Edvinsson S, Brostrom G. Change in food availability during pregnancy: Is it related to adult sudden death from cerebro‐and cardiovascular disease in offspring?. American Journal of Human Biology. 2000; 12(4):447-453. https://doi.org/10.1002/1520-6300(200007/08)12:4<447::AID-AJHB3>3.0.CO;2-M.

  • Huang C, Li Z, Wang M, Martorell R. Early life exposure to the 1959-1961 Chinese famine has long-term health consequences. The Journal of Nutrition. 2010; 140(10):1874-1878. https://doi.org/10.3945/jn.110.121293. PMid:20702751.

  • Bourguignon JP, Juul A, Franssen D, Fudvoye J, Pinson A, Parent AS. 2016. Contribution of the endocrine perspective in the evaluation of endocrine disrupting chemical effects: The case study of pubertal timing. Hormone Research in Paediatrics. 86(4):221-232. https://doi.org/10.1159/000442748. PMid:26799415.

  • Palanza P, Nagel SC, Parmigiani S, vom Saal FS. Perinatal exposure to endocrine disruptors: Sex, timing and behavioral endpoints. Current Opinion in Behavioral Sciences. 2016; 7:69-75. https://doi.org/10.1016/j.cobeha.2015.11.017. PMid:27019862 PMCid:PMC4805122.

  • Inagaki T, Smith N, Lee EK, Ramakrishnan S. Low dose exposure to Bisphenol A alters development of gonadotropin-releasing hormone 3 neurons and larval locomotor behavior in Japanese Medaka. Neurotoxicology. 2016; 52:188-197. https://doi.org/10.1016/j.neuro.2015.12.003. PMid:26687398.

  • McLellan D. Discussion of bisphenol A as an environmental endocrine disruptor: The low dose effect and governmental regulations concerning its use and disposal: A literature review. Revue Interdisciplinaire Des Sciences De La Santé-Interdisciplinary Journal of Health Sciences. 2016; 1(1):54-59. https://doi.org/10.18192/riss-ijhs.v1i1.1535.

  • Wang Q, Lam JC, Han J, Wang X, Guo Y, Lam PK, Zhou B. Developmental exposure to the organophosphorus flame retardant tris (1, 3-dichloro-2-propyl) phosphate: Estrogenic activity, endocrine disruption and reproductive effects on zebrafish. Aquatic Toxicology. 2015; 160:163-171. https://doi.org/10.1016/j.aquatox.2015.01.014. PMid:25637911.

  • Azzouz A, Rascon AJ, Ballesteros E. Simultaneous determination of parabens, alkylphenols, phenylphenols, bisphenol A and triclosan in human urine, blood and breast milk by continuous solid-phase extraction and gas chromatography-mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2016; 119:16-26. https://doi.org/10.1016/j.jpba.2015.11.024. PMid:26637951.

  • Raghavan AS, Sathyanarayana HP, Kailasam V, Padmanabhan S. Comparative evaluation of salivary bisphenol A levels in patients wearing vacuum-formed and Hawley retainers: An in-vivo study. American Journal of Orthodontics and Dentofacial Orthopedics. 2017; 151(3):471-476. https://doi.org/10.1016/j.ajodo.2016.07.022. PMid:28257731.

  • Frederiksen H, Jorgensen N, Andersson AM. Parabens in urine, serum and seminal plasma from healthy Danish men determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Journal of Exposure Science and Environmental Epidemiology. 2011; 21(3):262-271. https://doi.org/10.1038/jes.2010.6. PMid:20216574.

  • Takeuchi T, Tsutsumi O, Ikezuki Y, TAKAI Y, TAKETANI Y. Positive relationship between androgen and the endocrine disruptor, bisphenol A, in normal women and women with ovarian dysfunction. Endocrine Journal. 2004; 51(2):165-169. https://doi.org/10.1507/endocrj.51.165. PMid:15118266.

  • Szybiak A, Rutkowska A, Wilczewska K, Wasik A, Namiesnik J, Rachon D. Daily diet containing canned products significantly increases serum concentrations of endocrine disruptor bisphenol A in young women. Polish Archives of Internal Medicine. 2017; 127(4):278. https://doi.org/10.20452/pamw.4005. PMid:28436414.

  • Lathi RB, Liebert CA, Brookfield KF, Taylor JA, Vom Saal FS, Fujimoto VY, Baker VL. Conjugated bisphenol A in maternal serum in relation to miscarriage risk. Fertility and Sterility. 2014; 102(1):123-128. https://doi.org/10.1016/j.fertnstert.2014.03.024. PMid:24746738 PMCid:PMC4711263.

  • Tyagi V, Garg N, Mustafa MD, Banerjee BD, Guleria K. Organochlorine pesticide levels in maternal blood and placental tissue with reference to preterm birth: A recent trend in North Indian population. Environmental Monitoring and Assessment. 2015; 187(7):471. https://doi.org/10.1007/s10661-015-4369-x. PMid:26122123.

  • Lyall K, Croen LA, Sjodin A, Yoshida CK, Zerbo O, Kharrazi M, Windham GC. Polychlorinated biphenyl and organochlorine pesticide concentrations in maternal midpregnancy serum samples: association with autism spectrum disorder and intellectual disability. Environmental Health Perspectives. 2017; 125(3):474. https://doi.org/10.1289/ EHP277. PMid:27548254 PMCid:PMC5332182.

  • Choi G, Kim S, Kim S, Kim S, Choi Y, Kim HJ, Lee JJ, Kim SY, Lee S, Moon HB, Choi S. Occurrences of major Poly-Brominated Diphenyl Ethers (PBDEs) in maternal and fetal cord blood sera in Korea. Science of the Total Environment. 2014; 491:219-226. https://doi.org/10.1016/j.scitotenv.2014.02.071. PMid:24636800.

  • Zhao Y, Liu P, Wang J, Xiao X, Meng X, Zhang Y. Umbilical cord blood PBDEs concentrations are associated with placental DNA methylation. Environment International. 2016; 97:1-6. https://doi.org/10.1016/j.envint.2016.10.014. PMid:27768956.

  • Luo D, Pu Y, Tian H, Cheng J, Zhou T, Tao Y, Yuan J, Sun X, Mei S. Concentrations of organochlorine pesticides in umbilical cord blood and related lifestyle and dietary intake factors among pregnant women of the Huaihe River Basin in China. Environment International. 2016; 92:276-283. https://doi.org/10.1016/j.envint.2016.04.017. PMid:27123771.

  • Sudhanshu Shekhar, Surbhi Sood, Sadiya Showkat, Christy Lite, Anjalakshi Chandrasekhar, Mariappanadar Vairamani, Barathi S, Winkins Santosh. Detection of phenolic Endocrine Disrupting Chemicals (EDCs) from maternal blood plasma and amniotic fluid in Indian population. General and Comparative Endocrinology. 2017; 241:100-107. https://doi.org/10.1016/j.ygcen.2016.05.025. PMid:27235644.

  • Pinney SE, Mesaros CA, Snyder NW, Busch CM, Xiao R, Aijaz S, Ijaz N, Blair IA, Manson JM. Second trimester amniotic fluid bisphenol A concentration is associated with decreased birth weight in term infants. Reproductive Toxicology. 2017; 67:1-9. https://doi.org/10.1016/j.reprotox.2016.11.007. PMid:27829162 PMCid:PMC5303174.

  • Sengul SISE, Cevdet UGUZ. Nonylphenol in Human Breast Milk in Relation to Sociodemographic Variables, Diet, Obstetrics Histories and Lifestyle Habits in a Turkish Population. Iranian Journal of Public Health. 2017; 46(4):491. PMID: 28540265.

  • Inthavong C, Hommet F, Bordet F, Rigourd V, Guerin T, Dragacci S. Simultaneous liquid chromatography-tandem mass spectrometry analysis of brominated flame retardants (tetrabromobisphenol A and hexabromocyclododecane diastereoisomers) in French breast milk. Chemosphere. 2017; 186:762-769. https://doi.org/10.1016/j.chemosphere.2017.08.020. PMid:28821000.

  • Fernandez MF, Arrebola JP, Jimenez-Diaz I, Saenz JM, Molina-Molina JM, Ballesteros O, Kortenkamp A, Olea N. Bisphenol A and other phenols in human placenta from children with cryptorchidism or hypospadias. Reproductive Toxicology. 2016; 59:89-95. https://doi.org/10.1016/j.reprotox.2015.11.002. PMid:26602963.

  • Sood S, Shekhar S, Santosh W. Dimorphic placental stress: A repercussion of interaction between Endocrine Disrupting Chemicals (EDCs) and fetal sex. Medical Hypotheses. 2017; 99:73-75. https://doi.org/10.1016/j.mehy.2017.01.002. PMid:28110704.

  • Skinner M. Environmental epigenetic transgenerational inheritance and somatic epigenetic mitotic stability. Epigenetics. 2011; 6(7):838-842. https://doi.org/10.4161/epi.6.7.16537. PMid:21637037 PMCid:PMC5703187.

  • Dambal VY, Selvan KP, Lite C, Barathi S, Santosh W. Developmental toxicity and induction of vitellogenin in embryo-larval stages of zebrafish (Daniorerio) exposed to methyl Paraben. Ecotoxicology and Environmental Safety. 2017; 141:113-118. https://doi.org/10.1016/j.ecoenv.2017.02.048. PMid:28324817.

  • Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J. Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. Journal of Endocrinology. 2008; 196(1):101-112. https://doi.org/10.1677/JOE-07-0056. PMid:18180321.

  • Waddington C. The epigenotype. Endeavour. 1942; 1:18-20. https://doi.org/10.1093/ije/dyr184.

  • Russo VE, Martienssen RA, Riggs AD. Epigenetic mechanisms of gene regulation. Cold Spring Harbor Laboratory Press. 1996. https://doi.org/10.1017/s0016672397229320.

  • Seki Y, Yamaji M, Yabuta Y, Sano M, Shigeta M, Matsui Y, Saga Y, Tachibana M, Shinkai Y, Saitou M. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development. 2007; 134(14):2627-2638. https://doi.org/10.1242/dev.005611. PMid:17567665.

  • Tarantino LM, Sullivan PF, Meltzer-Brody S. Using animal models to disentangle the role of genetic, epigenetic, and environmental influences on behavioral outcomes associated with maternal anxiety and depression. Frontiers in Psychiatry. 2011; 2:10. https://doi.org/10.3389/fpsyt.2011.00044. PMid:21811473 PMCid:PMC3141357.

  • Kim MS, Kondo T, Takada I, Youn MY, Yamamoto Y, Takahashi S, Matsumoto T, Fujiyama S, Shirode Y, Yamaoka I, Kitagawa H. DNA demethylation in hormone-induced transcriptional derepression. Nature. 2009; 461(7266):1007-1012. https://doi.org/10.1038/nature08456. PMid:19829383.

  • Weber M, Schubeler D. Genomic patterns of DNA methylation: targets and function of an epigenetic mark. Current Opinion in Cell Biology. 2007; 19(3):273-280. https://doi.org/10.1016/j.ceb.2007.04.011. PMid:17466503.

  • Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE, Bestor TH. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science. 2006; 311(5759):395-398. https://doi.org/10.1126/science.1120976. PMid:16424344.

  • Newell-Price J, Clark AJ, King P. DNA methylation and silencing of gene expression. Trends in Endocrinology andoi.org/10.1016/j.scitotenv.2014.02.071. PMid:24636800. Metabolism. 2000; 11(4):142-148. https://doi.org/10.1016/S1043-2760(00)00248-4.

  • Hervouet E, Vallette FM, Cartron PF. Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics. 2009; 4(7):487-499. https://doi.org/10.4161/epi.4.7.9883. PMid:19786833.

  • Reik W, Walter J. Evolution of imprinting mechanisms: The battle of the sexes begins in the zygote. Nature Genetics. 2001a; 27(3):255-256. https://doi.org/10.1038/85804. PMid:11242103.

  • Reik W, Walter J. Genomic imprinting: parental influence on the genome. Nature Reviews Genetics. 2001b; 2(1):21- 32. https://doi.org/10.1038/35047554. PMid:11253064.

  • Tucker KL, Beard C, Dausmann J, Jackson-Grusby L, Laird PW, Lei H, Li E, Jaenisch, R. Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of nonimprinted genes. Genes and development. 1996; 10(8):1008-1020. https://doi.org/10.1101/gad.10.8.1008. PMid:8608936.

  • Santos F, Dean W. Epigenetic reprogramming during early development in mammals. Reproduction. 2004; 127(6):643- 651. https://doi.org/10.1530/rep.1.00221. PMid:15175501.

  • Mayer W, Niveleau A, Walter J, Fundele R, Haaf T. Embryogenesis: Demethylation of the zygotic paternal genome. Nature. 2000; 403(6769):501-502. https://doi.org/10.1038/35000656. PMid:10676950.

  • Dean W, Santos F, Reik W. February. Epigenetic Reprogramming in Early Mammalian Development and Following Somatic Nuclear Transfer. In: Seminars in Cell and Developmental Biology; 2003. 14(1), p. 93-100. https://doi.org/10.1016/S1084-9521(02)00141-6.

  • Dean W, Santos F, Stojkovic M, Zakhartchenko V, Walter J, Wolf E, Reik W. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proceedings of the National Academy of Sciences. 2001; 98(24):13734-13738. https://doi.org/10.1073/pnas.241522698. PMid:11717434 PMCid:PMC61110.

  • Bestor TH. The DNA methyltransferases of mammals. Human Molecular Genetics. 2000; 9(16):2395-2402. https://doi.org/10.1093/hmg/9.16.2395. PMid:11005794.

  • Santos F, Hendrich B, Reik W, Dean W. Dynamic reprogramming of DNA methylation in the early mouse embryo. Developmental Biology. 2002; 241(1):172-182. https://doi.org/10.1006/dbio.2001.0501. PMid:11784103.

  • Ginsburg MALKA, Snow MH, McLaren ANNE. Primordial germ cells in the mouse embryo during gastrulation. Development. 1990; 110(2):521-528. https://doi.org/10.1242/dev.110.2.521. PMid:2133553.

  • Lees-Murdock DJ, Walsh CP. DNA methylation reprogramming in the germ line. Epigenetics. 2008; 3(1):5- 13. https://doi.org/10.4161/epi.3.1.5553. PMid:18259118.

  • Iguchi-Ariga SM, Schaffner W. CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes and Development. 1989; 3(5):612-619. https://doi.org/10.1101/gad.3.5.612. PMid:2545524.

  • Campanero MR, Armstrong MI, Flemington EK. CpG methylation as a mechanism for the regulation of E2F activity. Proceedings of the National Academy of Sciences. 2000; 97(12):6481-6486. https://doi.org/10.1073/pnas.100340697. PMid:10823896 PMCid:PMC18629.

  • Miranda TB, Jones PA. DNA methylation: the nuts and bolts of repression. Journal of Cellular Physiology. 2007; 213(2):384-390. https://doi.org/10.1002/jcp.21224. PMid:17708532.

  • Jones PL, Veenstra GCJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genetics. 1998; 19(2):187-191. https://doi.org/10.1038/561. PMid:9620779.

  • Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998; 393(6683):386-389. https://doi.org/10.1038/30764. PMid:9620804.

  • Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP. Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nature Genetics. 1999; 23(1):62-66. https://doi.org/10.1038/12664. PMid:10471500.

  • Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T. The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. Journal of Biological Chemistry. 2003; 278(6):4035-4040. https://doi.org/10.1074/jbc.M210256200. PMid:12427740.

  • Bogdanovic O, Veenstra GJC. DNA methylation and methyl- CpG binding proteins: Developmental requirements and function. Chromosoma. 2009; 118(5):549-565. https://doi.org/10.1007/s00412-009-0221-9. PMid:19506892 PMCid:PMC2729420.

  • Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 2004; 116(2):281-297. https://doi.org/10.1016/S0092-8674(04)00045-5.

  • Siomi H, Siomi MC. Posttranscriptional regulation of microRNA biogenesis in animals. Molecular Cell. 2010; 38(3):323-332. https://doi.org/10.1016/j.molcel.2010.03.013. PMid:20471939.

  • Carrington JC, Ambros V. Role of microRNAs in plant and animal development. Science. 2003; 301(5631):336-338. https://doi.org/10.1126/science.1085242. PMid:12869753.

  • Ambros V. The functions of animal microRNAs. Nature. 2004; 431(7006):350. https://doi.org/10.1038/nature02871. PMid:15372042.

  • Hatfield SD, Shcherbata HR, Fischer KA, Nakahara K. Stem cell division is regulated by the microRNA pathway. Nature. 2005; 435(7044):974. https://doi.org/10.1038/nature03816. PMid:15944714.

  • Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001; 294(5543):853-858. https://doi.org/10.1126/science.1064921. PMid:11679670.

  • Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: stepwise processing and subcellular localization. The EMBO Journal. 2002; 21(17):4663-4670. https://doi.org/10.1093/emboj/cdf476. PMid:12198168 PMCid:PMC126204.

  • Mourelatos Z, Dostie J, Paushkin S, Sharma A, Charroux B, Abel L, Rappsilber J, Mann M, Dreyfuss G. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes and Development. 2002; 16(6):720-728. https://doi.org/10.1101/gad.974702. PMid:11914277 PMCid:PMC155365.

  • Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Radmark O, Kim S, Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003; 425(6956):415-419. https://doi.org/10.1038/nature01957. PMid:14508493.

  • Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN. The Drosha- DGCR8 complex in primary microRNA processing. Genes and Development. 2004; 18(24):3016-3027. https://doi.org/10.1101/gad.1262504. PMid:15574589 PMCid:PMC535913.

  • Zeng Y, Yi R, and Cullen BR. Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha. The EMBO Journal. 2005; 24(1):138-148. https://doi.org/10.1038/sj.emboj.7600491. PMid:15565168 PMCid:PMC544904.

  • Martin R, Smibert P, Yalcin A, Tyler D.M, Schafer U, Tuschl T, Lai EC. A Drosophila pasha mutant distinguishes the canonical microRNA and mirtron pathways. Molecular and Cellular Biology. 2009; 29(3):861-870. https://doi.org/10.1128/MCB.01524-08. PMid:19047376 PMCid:PMC2630677.

  • Chendrimada TP, Gregory RI, Kumaraswamy E, Norman J, Cooch N, Nishikura K, Shiekhattar R. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature. 2005; 436(7051):740-744. https://doi.org/10.1038/nature03868. PMid:15973356 PMCid:PMC2944926.

  • Peters L, Meister G. Argonaute proteins: Mediators of RNA silencing. Molecular cell. 2007; 26(5):611-623. https://doi.org/10.1016/j.molcel.2007.05.001. PMid:17560368.

  • Jakymiw A, Lian S, Eystathioy T, Li S, Satoh M, Hamel JC, Fritzler MJ, Chan EK. Disruption of GW bodies impairs mammalian RNA interference. Nature Cell Biology. 2005; 7(12):1267-1274. https://doi.org/10.1038/ncb1334. PMid:16284622.

  • Behm-Ansmant I, Rehwinkel J, Doerks T, Stark A, Bork P, Izaurralde E. mRNA degradation by miRNAs and GW182 requires both CCR4: NOT deadenylase and DCP1: DCP2 decapping complexes. Genes and Development. 2006; 20(14):1885-1898. https://doi.org/10.1101/gad.1424106. PMid:16815998 PMCid:PMC1522082.

  • Chu CY, Rana TM. Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54. PLoS Biology. 2006; 4(7):e210. https://doi.org/10.1371/journal. pbio.0040210. PMid:16756390 PMCid:PMC1475773.

  • Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: MicroRNA biogenesis pathways and their regulation. Nature Cell Biology. 2009; 11(3):228-234. https://doi.org/10.1038/ncb0309-228. PMid:19255566.

  • Ha M, Kim VN. Regulation of microRNA biogenesis. Nature Reviews Molecular Cell Biology. 2014; 15(8):509- 524. https://doi.org/10.1038/nrm3838. PMid:25027649.

  • Abdelfattah AM, Park C, Choi MY. Update on noncanonical microRNAs. Biomolecular Concepts. 2014; 5(4):275-287. https://doi.org/10.1515/bmc-2014-0012. PMid:25372759 PMCid:PMC4343302.

  • Havens MA, Reich AA, Duelli DM, Hastings ML. Biogenesis of mammalian microRNAs by a non-canonical processing pathway. Nucleic Acids Research. 2012; 40(10):4626- 4640. https://doi.org/10.1093/nar/gks026. PMid:22270084 PMCid:PMC3378869.

  • Newbold RR, Padilla-Banks E, Jefferson WN. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology. 2006; 147(6):s11-s17. https://doi.org/10.1210/en.2005- 1164. PMid:16690809.

  • Newbold RR, Padilla-Banks E, Snyder RJ, Phillips TM, Jefferson WN. Developmental exposure to endocrine disruptors and the obesity epidemic. Reproductive Toxicology. 2007; 23(3):290-296. https://doi.org/10.1016/j.reprotox.2006.12.010. PMid:17321108 PMCid:PMC1931509.

  • Bateson P, Barker D, Clutton-Brock T, Deb D, Dudine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J. Developmental plasticity and human health. Nature. 2004; 430(6998):419-421. https://doi.org/10.1038/nature02725. PMid:15269759.

  • Warri A, Saarinen N, Makela S, Hilakivi-Clarke L. The role of early life genistein exposures in modifying breast cancer risk. British Journal of Cancer. 2008; 98(9):1485-1493. https://doi.org/10.1038/sj.bjc.6604321. PMid:18392054 PMCid:PMC2391102.

  • Weaver I, Cervoni N, Champagne F, Alessio AD, Sharma S, Seckl J, Dymov S, Szyf M, Meaney M. Epigenetic programming by maternal behavior. Nature Neuroscience. 2004; 7(8):847-854. https://doi.org/10.1038/nn1276. PMid:15220929.

  • Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ. Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology. 2006; 147(6):2909-2915. https://doi.org/10.1210/en.2005-1119. PMid:16513834.

  • Meaney MJ Szyf M. Maternal care as a model for experience-dependent chromatin plasticity? Trends in Neurosciences. 2005; 28(9):456-463. https://doi.org/10.1016/j.tins.2005.07.006. PMid:16054244.

  • Beery AK, Francis DD. Adaptive significance of natural variations in maternal care in rats: A translational perspective. Neuroscience and Biobehavioral Reviews. 2011; 35(7):1552-1561. https://doi.org/10.1016/j.neubiorev.2011.03.012. PMid:21458485 PMCid:PMC3104121.

  • Curley JP, Champagne FA. Influence of maternal care on the developing brain: Mechanisms, temporal dynamics and sensitive periods. Frontiers in neuroendocrinology. 2016; 40:52-66. https://doi.org/10.1016/j.yfrne.2015.11.001. PMid:26616341 PMCid:PMC4783284.

  • Dolinoy DC. Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environmental Health Perspectives. 2006; 114(4):567. https://doi.org/10.1289/ehp.8700. PMid:16581547 PMCid:PMC1440782

  • Yenbutr P, Hilakivi-Clarke L, Passaniti A. Hypomethylation of an exon I estrogen receptor CpG island in spontaneous and carcinogen-induced mammary tumorigenesis in the rat. Mechanisms of Ageing and Development. 1998; 106(1- 2):93-102. https://doi.org/10.1016/S0047-6374(98)00093-1

  • Keyes MK, Jang H, Mason JB, Liu Z, Crott JW, Smith DE, Friso S, Woon CS. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. The Journal of Nutrition Biochemical, Molecular, and Genetic Mechanisms. 2007; 1713-1717. https://doi.org/10.1017/s0007114510000322. PMid:17585020

  • Kotsopoulos J, Sohn KJ, Kim YI. Postweaning dietary folate deficiency provided through childhood to puberty permanently increases genomic DNA methylation in adult rat liver. The Journal of Nutrition. 2008. 138(4):703- 709. https://doi.org/10.1093/jn/138.4.703. PMid:18356324.

  • Kinsella MT, Monk C. Impact of maternal stress, depression and anxiety on fetal neurobehavioral development. Clinical Obstetrics and Gynecology. 2009; 52(3):425. https://doi.org/10.1097/GRF.0b013e3181b52df1. PMid:19661759 PMCid:PMC3710585.

  • Zucchi FC, Yao Y, Ward ID, Ilnytskyy Y, Olson DM, Benzies K, Kovalchuk I, Kovalchuk O, Metz GA. Maternal stress induces epigenetic signatures of psychiatric and neurological diseases in the offspring. PloS one. 2013; 8(2):e56967. https://doi.org/10.1371/journal.pone.0056967. PMid:23451123 PMCid:PMC3579944.

  • Harper L. Epigenetic inheritance and the intergenerational transfer of experience. Psychological Bulletin. 2005; 131(3):340. https://doi.org/10.1037/0033-2909.131.3.340. PMid:15869332.

  • Skinner MK. Endocrine disruptor induction of epigenetic transgenerational inheritance of disease. Molecular and Cellular Endocrinology. 2014; 398(1):4-12. https://doi.org/10.1016/j.mce.2014.07.019. PMid:25088466 PMCid:PMC4262585.

  • Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science. 2005; 308(5727):1466-1469. https://doi.org/10.1126/science.1108190. PMid:15933200.

  • Guerrero-Bosagna C, Settles M, Lucker B. Skinner M. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS ONE. 2010; 5(9):e13100. https://doi.org/10.1371/journal.pone.0013100. PMid:20927350 PMCid:PMC2948035

  • Salian S, Doshi T, Vanage G. Impairment in protein expression profile of testicular steroid receptor coregulators in male rat offspring perinatally exposed to Bisphenol A. Life Sciences. 2009a; 85(1-2):11-18. https://doi.org/10.1016/j.lfs.2009.04.005. PMid:19379760.

  • Bruner-Tran K, Osteen K. Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reproductive Toxicology. 2011; 31(3):344-350. https://doi.org/10.1016/j.reprotox.2010.10.003. PMid:20955784 PMCid:PMC3044210.

  • Matthews S, Phillips D. Transgenerational inheritance of stress pathology. Experimental Neurology. 2012; 233(1):95-101. https://doi.org/10.1016/j.expneurol.2011.01.009. PMid:21281632.

  • Anway M, Leathers C, Skinner M. Endocrine disruptor vinclozolin induced epigenetic transgenerational adultonset disease. Endocrinology. 2006; 147(12):5515-5523. https://doi.org/10.1210/en.2006-0640. PMid:16973726 PMCid:PMC5940332.

  • Anway MD, Skinner MK. Epigenetic programming of the germ line: Effects of endocrine disruptors on the development of transgenerational disease. Reproductive Biomedicine Online. 2008. 16(1):23-25. https://doi.org/10.1016/S1472-6483(10)60553-6.

  • Nilsson E, Anway M, Stanfield J, Skinner M. Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease. Reproduction. 2008; 135(5):713-721. https://doi.org/10.1530/REP-07-0542. PMid:18304984 PMCid:PMC5703189.

  • Manikkam M, Tracey R, Guerrero-Bosagna C, Skinner M. Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations. PLoS ONE. 2013; 8(1):e55387. https://doi.org/10.1371/journal.pone.0055387. PMid:23359474 PMCid:PMC3554682.

  • Pocar P, Fiandanese N, Berrini A, Secchi C, Borromeo V. Maternal exposure to di (2-ethylhexyl)phthalate (DEHP) promotes the transgenerational inheritance of adult-onset reproductive dysfunctions through the female germline in mice. Toxicology and Applied Pharmacology. 2017; 322:113-121. https://doi.org/10.1016/j.taap.2017.03.008. PMid:28286118.

  • Doyle T, Bowman J, Windell V, McLean D, Kim K. Transgenerational effects of Di-(2-ethylhexyl) phthalate on testicular germ cell associations and spermatogonial stem cells in mice1. Biology of Reproduction. 2013; 88(5):10. https://doi.org/10.1095/biolreprod.112.106104. PMid:23536373 PMCid:PMC4013901.

  • Salian S, Doshi T, Vanage G. Perinatal exposure of rats to Bisphenol A affects the fertility of male offspring. Life Sciences. 2009b.; 85(21-22):742-752. https://doi.org/10.1016/j.lfs.2009.10.004. PMid:19837096.

  • Wolstenholme J, Edwards M, Shetty S, Gatewood J, Taylor J, Rissman E, Connelly J. Gestational exposure to bisphenol a produces transgenerational changes in behaviors and gene expression. Endocrinology. 2012; 153(8):3828-3838. https://doi.org/10.1210/en.2012-1195. PMid:22707478 PMCid:PMC3404345.

  • Skinner MK. Role of epigenetics in developmental biology and transgenerational inheritance. Birth Defects Research Part C: Embryo Today: Reviews. 2011; 93(1):51-55. https://doi.org/10.1002/bdrc.20199. PMid:21425441 PMCid:PMC5703206.

  • Grun F, Blumberg B. Endocrine disrupters as obesogens. Molecular and Cellular Endocrinology. 2009; 304(1):19-29. https://doi.org/10.1016/j.mce.2009.02.018. PMid:19433244 PMCid:PMC2713042.

  • Barouki R, Gluckman PD, Grandjean P, Hanson M, Heindel JJ. Developmental origins of non-communicable disease: Implications for research and public health. Environmental Health. 2012; 11(1):42. https://doi.org/10.1186/1476-069X-11-42. PMid:22715989 PMCid:PMC3384466.

  • Yolton K, Xu Y, Strauss D, Altaye M, Calafat AM, Khoury J. Prenatal exposure to bisphenol A and phthalates and infant neurobehavior. Neurotoxicology and teratology. 2011; 33(5):558-566. https://doi.org/10.1016/j.ntt.2011.08.003. PMid:21854843 PMCid:PMC3183357.

  • Rier SE, Zarmakoupis PN, Hu XIAOLING, Becker JL. Dysregulation of interleukin-6 responses in ectopic endometrial stromal cells: Correlation with decreased soluble receptor levels in peritoneal fluid of women with endometriosis. The Journal of Clinical Endocrinology and Metabolism. 1995; 80(4):1431-1437. https://doi.org/10.1210/jcem.80.4.7714120. PMid:7714120.

  • Boberg J, Mandrup KR, Jacobsen PR, Isling LK, Hadrup N, Berthelsen L, Elleby A, Kiersgaard M, Vinggaard AM, Hass U, Nellemann C. Endocrine disrupting effects in rats perinatally exposed to a dietary relevant mixture of phytoestrogens. Reproductive Toxicology. 2013; 40:41-51. https://doi.org/10.1016/j.reprotox.2013.05.014. PMid:23770295.

  • Masuo Y, Ishido M. Neurotoxicity of endocrine disruptors: Possible involvement in brain development and neurodegeneration. Journal of Toxicology and Environmental Health, Part B. 2011; 14(5-7):346-369. https://doi.org/10.1080/1 0937404.2011.578557. PMid:21790316.

  • Kundakovic M, Gudsnuk K, Franks B, et al. Sex-specific epigenetic disruption and behavioral changes following low-dose in utero bisphenol A exposure. Proceedings of the National Academy of Sciences. 2013; 110(24):9956-9961. https://doi.org/10.1073/pnas.1214056110. PMid:23716699 PMCid:PMC3683772.

  • Ma Y, Xia W, Wang DQ, et al. Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. Diabetologia. 2013; 56(9):2059-2067. https://doi.org/10.1007/s00125-013-2944-7. PMid:23748860.

  • Bromer JG, Zhou Y, Taylor MB, et al. Bisphenol-A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. The FASEB Journal. 2010; 24(7):2273-2280. https://doi.org/10.1096/fj.09-140533. PMid:20181937 PMCid:PMC3230522.

  • Strakovsky RS, Wang H, Engeseth NJ, et al. Developmental Bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis. Toxicology and Applied Pharmacology. 2015; 284(2):101-112. https://doi.org/10.1016/j.taap.2015.02.021. PMid:25748669 PMCid:PMC4520316.

  • Chao HH, Zhang XF, Chen B, et al. Bisphenol A exposure modifies methylation of imprinted genes in mouse oocytes via the estrogen receptor signaling pathway. Histochemistry and Cell Biology. 2012; 137(2):249-259. https://doi.org/10.1007/s00418-011-0894-z. PMid:22131059.

  • Kovanecz I, Gelfand R, Masouminia M, et al. Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription. International Journal of Impotence Research. 2014; 26(2):67-75. https://doi.org/10.1038/ijir.2013.37. PMid:24305612 PMCid:PMC4098849.

  • 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):74-82. https://doi.org/10.1016/j.tox.2011.07.011. PMid:21827818.

  • Jadhav RR, Santucci-Pereira J, Wang YV, et al. DNA Methylation Targets Influenced by Bisphenol A and/ or Genistein Are Associated with Survival Outcomes in Breast Cancer Patients. Genes (Basel). 2017; 8(5):144. https://doi.org/10.3390/genes8050144. PMid:28505145 PMCid:PMC5448018.

  • Doherty LF, Bromer JG, Zhou Y, et al. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: An epigenetic mechanism linking endocrine disruptors to breast cancer. Hormones and Cancer. 2010; 1(3):146-155. https://doi.org/10.1007/s12672-010-0015-9. PMid:21761357 PMCid:PMC3140020.

  • Zama AM, Uzumcu M. Fetal and neonatal exposure to the endocrine disruptor methoxychlor causes epigenetic alterations in adult ovarian genes. Endocrinology. 2009; 2009(10):4681-91. https://doi.org/10.1210/en.2009-0499. PMid:19589859 PMCid:PMC2754680.

  • Bromer JG, Wu J, Zhou Y, Taylor HS. Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: An epigenetic mechanism for altered developmental programming. Endocrinology. 2009; 150(7):3376-3382. https://doi.org/10.1210/en.2009-0071. PMid:19299448 PMCid:PMC2703508.

  • Chen J, Wu S, Wen S, et al. The mechanism of environmental endocrine disruptors (DEHP) induces epigenetic transgenerational inheritance of cryptorchidism. PloS One. 2015; 10(6):e0126403. https://doi.org/10.1371/journal.pone.0126403. PMid:26035430 PMCid:PMC4452760.

  • Iqbal K, Tran DA, Li AX, et al. Deleterious effects of endocrine disruptors arecorrected in the mammalian germline by epigenome reprogramming. Genome Biology. 2015; 16(1):59. https://doi.org/10.1186/s13059-015-0619-z. PMid:25853433 PMCid:PMC4376074.

  • Song Y, Wu N, Wang S, et al. Transgenerational impaired male fertility with an Igf2 epigenetic defect in the rat are induced by the endocrine disruptor p, p′-DDE. Human Reproduction. 2014; 29(11):2512-2521. https://doi.org/10.1093/humrep/deu208. PMid:25187598.

  • Chanyshev MD, Kosorotikov NI, Titov SE, et al. Expression of microRNAs, CYP1A1 and CYP2B1 in the livers and ovaries of female rats treated with DDT and PAHs. Life Sciences. 2014; 103(2):95-100. https://doi.org/10.1016/j.lfs.2014.03.031. PMid:24727239.

  • Meunier L, Siddeek B, Vega A, et al. Perinatal programming of adult rat germ cell death after exposure to xenoestrogens: Role of microRNA miR-29 family in the down-regulation of DNA methyltransferases and Mcl-1. Endocrinology. 2012; 153(4):1936-1947. https://doi.org/10.1210/en.2011-1109. PMid:22334722.

  • Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environmental Health Perspectives. 2006; 114(4):567. https://doi.org/10.1289/ehp.8700. PMid:16581547 PMCid:PMC1440782.

  • Kirchner S, Kieu T, Chow C, et al. Prenatal exposure to the environmental obesogentributyltin predisposes multipotent stem cells to become adipocytes. Molecular Endocrinology. 2010; 24(3):526-539. https://doi.org/10.1210/me.2009-0261. PMid:20160124 PMCid:PMC2840805.

  • Strakovsky RS, Lezmi S, Shkoda I, et al. In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge. The Journal of Nutritional Biochemistry. 2015; 26(11):1208- 1220. https://doi.org/10.1016/j.jnutbio.2015.05.012. PMid:26188368 PMCid:PMC4631689.

  • Alworth LC, Howdeshell KL, Ruhlen RL, et al. Uterine responsiveness to estradiol and DNA methylation are altered by fetal exposure to diethylstilbestrol and methoxychlor in CD-1 mice: Effects of low versus high doses. Toxicology and Applied Pharmacology. 2002; 183(1):10-22. https://doi.org/10.1006/taap.2002.9459. PMid:12217638.

  • Lyn-Cook BD, Blann E, Payne PW, et al. Methylation profile and amplification of proto-oncogenes in rat pancreas induced with phytoestrogens. Proceedings of the Society for Experimental Biology and Medicine. 1995; 208(1):116-119. https://doi.org/10.3181/00379727-208-43842. PMid:7534422.

  • Buckley J, Willingham E, Agras K, Baskin LS. Embryonic exposure to the fungicide vinclozolin causes virilization of females and alteration of progesterone receptor expression in vivo: An experimental study in mice. Environmental Health. 2006; 5(1):4. https://doi.org/10.1186/1476-069X-5-4. PMid:16504050 PMCid:PMC1403752.


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  • Alterations in the Epigenetic Landscape Underlying Later-Life Health Effects Due to In-utero Exposure to Endocrine Disrupting Chemicals: A Review of Outcomes from Mice to Men

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Authors

S. Winkins Santosh
P.G. & Research Department of Advanced Zoology and Biotechnology, Government College for Men, Chennai − 600035, Tamil Nadu, India
Christy Lite
Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India
Glancis Luzeena Raja
Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India
K. Divya Subhashree
Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India
Kamalini Esther Kantayya
Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India
S. Barathi
Endocrine Disruption and Reproductive Toxicology (EDART) Laboratory, SRM Institute of Science and Technology, Chennai − 603203, Tamil Nadu, India

Abstract


Widespread persistence of Endocrine Disrupting Chemicals (EDCs) in the environment has mandated the need to study their potential long-term effects on human health, after acute as well aschronic exposures. The particular focus is on in utero exposure to EDCs in rodent models to look at altered epigenetic programming to result in transgenerational effects in later life of the offspring. This potentially contributes to reproductive and immune dysfunctions, obesity, cancer, and altered brain development and neurobehavioral outcomes. The literature to date establishes the transgenerational effects associated with in utero exposure to EDCs in rodent models. Hence, the aim of this review is to provide a comprehensive overview of epigenetic programming and its regulation in mammals, specially focussing on epigenetic plasticity and susceptibility to exogenous endocrine-active chemicals, EDCs, during the early developmental period, and carried forward to later life using rodent models. The available reports suggest that the key mechanism behind the long-term impact of EDCs is caused by alterations in the epigenetic programming machinery, leading to dysregulated gene expression during adult life. Studies have reported the effect of prenatal exposure to EDCs in the ovarian microRNA expression and function, highlighting ovary as an organ undergoing in utero programming. It ascertains the heightened sensitivity of the organ to exogenous hormone-active compounds, particularly during early development. In addition to this, another key aspect in this review is increased susceptibility of the brain when exposed to even minute quantities of EDCs during embryonic development, resulting in profound alterations in the structural organization of the brain and neurobehavior. Detailed analyses of variables such as folic acid and phytoestrogen content in maternal diet need to be considered as crucial factors while designing experiments and therapeutic interventions. Apart from this, appropriate animal handling during the experimental procedures to eliminate stress in animal models to ensure unbiased results is recommended.

Keywords


Adult Health, Endocrine Disrupting Chemicals (EDCs), Epigenetic Programming, Intrauterine Exposure.

References





DOI: https://doi.org/10.18311/jer%2F2021%2F28038