The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells may be extremely useful in bettering the understanding of epigenetic effects on human development, health and disease, because the formation of embryoid bodies in vitro is very similar to the early stage of embryogenesis.
References
[1]
Halden, R.U. Plastics and health risks. Annu. Rev. Public Health 2010, 31, 179–194.
[2]
Heudorf, U.; Mersch-Sundermann, V.; Angerer, J. Phthalates: Toxicology and exposure. Int. J. Hyg. Environ. Health 2007, 210, 623–634.
[3]
Wormuth, M.; Scheringer, M.; Vollenweider, M.; Hungerbühler, K. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 2006, 26, 803–824.
[4]
Thomas, J.A.; Thomas, M.J.; Gangolli, S.D. Biological effects of di-(2-ethylhexyl) phthalate and other phthalic acid esters. Crit. Rev. Toxicol 1984, 13, 283–317.
[5]
Dolinoy, D.C.; Jirtle, R.L. Environmental epigenomics in human health and disease. Environ. Mol. Mutagen 2008, 49, 4–8.
[6]
Anway, M.D.; Rekow, S.S.; Skinner, M.K. Transgenerational epigenetic programming of the embryonic testis transcriptome. Genomics 2008, 91, 30–40.
[7]
Schwartz, D.; Collins, F. Environmental biology and human disease. Science 2007, 316, 695–696.
[8]
Perera, F.; Herbstman, J. Prenatal environmental exposures, epigenetics, and disease. Reprod. Toxicol 2011, 31, 363–373.
[9]
Liu, L.; Li, Y.; Tollefsbol, T.O. Gene-environment interactions and epigenetic basis of human diseases. Curr. Issues Mol. Biol 2008, 10, 25–36.
[10]
Choudhuri, S.; Cui, Y.; Klaassen, C.D. Molecular targets of epigenetic regulation and effectors of environmental influences. Toxicol. Appl. Pharmacol 2010, 245, 378–393.
[11]
Kundakovic, M.; Champagne, F.A. Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav. Immun 2011, 25, 1084–1093.
[12]
Baccarelli, A.; Bollati, V. Epigenetics and environmental chemicals. Curr. Opin. Pediatr 2009, 21, 243–251.
[13]
Shelby, M.D. NTP-CERHR monograph on the potential human reproductive and developmental effects of bisphenol A. NTP CERHR MON 2008, 22, . passim.
[14]
Talsness, C.E.; Andrade, A.J.M.; Kuriyama, S.N.; Taylor, J.A.; vom Saal, F.S. Components of plastic: Experimental studies in animals and relevance for human health. Phil. Trans. Biol. Sci 2009, 364, 2079–2096.
[15]
Rubin, B.S. Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects. J. Steroid Biochem. Mol. Biol 2011, 127, 27–34.
[16]
Lang, I.A.; Galloway, T.S.; Scarlett, A.; Henley, W.E.; Depledge, M.; Wallace, R.B.; Melzer, D. Association of urinary bisphenol a concentration with medical disorders and laboratory abnormalities in adults. J. Am. Med. Assoc 2008, 300, 1303–1310.
[17]
Welshons, W.V.; Nagel, S.C.; vom Saal, F.S. Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology 2006, 147, s56–s69.
Shelby, M.D. NTP-CERHR monograph on the potential human reproductive and developmental effects of di-(2-ethylhexyl) phthalate (DEHP). NTP CERHR MON 2006, 18, . II-iii-xiii passim.
[20]
Swan, S.H.; Main, K.M.; Liu, F.; Stewart, S.L.; Kruse, R.L.; Calafat, A.M.; Mao, C.S.; Redmon, J.B.; Ternand, C.L.; Sullivan, S.; et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ. Health Perspect 2005, 113, 1056–1061.
[21]
Martino-Andrade, A.J.; Chahoud, I. Reproductive toxicity of phthalate esters. Mol. Nutr. Food Res 2010, 54, 148–157.
[22]
Christen, V.; Crettaz, P.; Oberli-Schr？mmli, A.; Fent, K. Antiandrogenic activity of phthalate mixtures: Validity of concentration addition. Toxicol. Appl. Pharmacol 2012, 259, 169–176.
[23]
Genuis, S.J.; Beesoon, S.; Birkholz, D.; Lobo, R.A. Human excretion of bisphenol A: Blood, urine, and sweat (BUS) study. J. Environ. Public Health 2012, 2012, 185731.
[24]
Davis, A.P.; Murphy, C.G.; Saraceni-Richards, C.A.; Rosenstein, M.C.; Wiegers, T.C.; Mattingly, C.J. Comparative toxicogenomics database: A knowledgebase and discovery tool for chemical-gene-disease networks. Nucleic Acids Res 2009, 37, D786–D792.
[25]
Singh, S.; Li, S.S.-L. Phthalates: Toxicogenomics and inferred human diseases. Genomics 2011, 97, 148–157.
[26]
Singh, S.; Li, S.S.-L. Bisphenol A and phthalates exhibit similar toxicogenomics and health effects. Gene 2012, 494, 85–91.
[27]
Dietert, R.R.; DeWitt, J.C.; Germolec, D.R.; Zelikoff, J.T. Breaking patterns of environmentally influenced disease for health risk reduction: Immune perspectives. Environ. Health Perspect 2010, 118, 1091–1099.
[28]
Morgan, H.D.; Sutherland, H.G.E.; Martin, D.I.K.; Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet 1999, 23, 314–318.
[29]
Dolinoy, D.C.; Huang, D.; Jirtle, R.L. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc. Natl. Acad. Sci. USA 2007, 104, 13056–13061.
[30]
Ho, S.-M.; Tang, W.-Y.; Belmonte de Frausto, J.; Prins, G.S. Developmental exposure to estradiol and bisphenol a increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 2006, 66, 5624–5632.
[31]
Prins, G.S.; Tang, W.-Y.; Belmonte, J.; Ho, S.-M. Developmental exposure to bisphenol a increases prostate cancer susceptibility in adult rats: Epigenetic mode of action is implicated. Fertil. Steril 2008, 89, e41.
[32]
Tang, W.-Y.; Morey, L.M.; Cheung, Y.Y.; Birch, L.; Prins, G.S.; Ho, S.-M. Neonatal exposure to estradiol/bisphenol A alters promoter methylation and expression of Nsbp1 and Hpcal1 genes and transcriptional programs of Dnmt3a/b and Mbd2/4 in the rat prostate gland throughout life. Endocrinology 2012, 153, 42–55.
[33]
Doshi, T.; Mehta, S.S.; Dighe, V.; Balasinor, N.; Vanage, G. Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. Toxicology 2011, 289, 74–82.
[34]
Bromer, J.G.; Zhou, Y.; Taylor, M.B.; Doherty, L.; Taylor, H.S. Bisphenol—A exposure in utero leads to epigenetic alterations in the developmental programming of uterine estrogen response. FASEB J 2010, 24, 2273–2280.
[35]
Yaoi, T.; Itoh, K.; Nakamura, K.; Ogi, H.; Fujiwara, Y.; Fushiki, S. Genome-wide analysis of epigenomic alterations in fetal mouse forebrain after exposure to low doses of bisphenol A. Biochem. Biophys. Res. Comm 2008, 376, 563–567.
[36]
Weng, Y.-I.; Hsu, P.-Y.; Liyanarachchi, S.; Liu, J.; Deatherage, D.E.; Huang, Y.-W.; Zuo, T.; Rodriguez, B.; Lin, C.-H.; Cheng, A.-L.; et al. Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol. Appl. Pharmacol 2010, 248, 111–121.
[37]
Doherty, L.; Bromer, J.; Zhou, Y.; Aldad, T.; Taylor, H. 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. Horm. Cancer 2010, 1, 146–155.
[38]
Vire, E.; Brenner, C.; Deplus, R.; Blanchon, L.; Fraga, M.; Didelot, C.; Morey, L.; van Eynde, A.; Bernard, D.; Vanderwinden, J.-M.; et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature 2006, 439, 871–874.
[39]
Avissar-Whiting, M.; Veiga, K.R.; Uhl, K.M.; Maccani, M.A.; Gagne, L.A.; Moen, E.L.; Marsit, C.J. Bisphenol A exposure leads to specific microRNA alterations in placental cells. Reprod. Toxicol 2010, 29, 401–406.
[40]
Cho, H.; Kim, S.; Park, H.-W.; Oh, M.-J.; Yu, S.; Lee, S.; Park, C.; Han, J.; Oh, J.-H.; Hwang, S.; et al. A relationship between miRNA and gene expression in the mouse sertoli cell line after exposure to bisphenol A. BioChip J 2010, 4, 75–81.
[41]
Chan Kang, S.; Mu Lee, B. DNA methylation of estrogen receptor α gene by phthalates. J. Toxicol. Environ. Health A 2005, 68, 1995–2003.
[42]
Wu, S.; Zhu, J.; Li, Y.; Lin, T.; Gan, L.; Yuan, X.; Xu, M.; Wei, G. Dynamic effect of di-2-(ethylhexyl) phthalate on testicular toxicity: Epigenetic changes and their impact on gene expression. Int. J. Toxicol 2010, 29, 193–200.
[43]
Kundakovic, M.; Champagne, F.A. Epigenetic perspective on the developmental effects of bisphenol A. Brain Behav. Immun 2011, 25, 1084–1093.
[44]
Manikkam, M.; Guerrero-Bosagna, C.; Tracey, R.; Haque, M.M.; Skinner, M.K. Transgenerational actions of environmental compounds on reproductive disease and identification of epigenetic biomarkers of ancestral exposures. PLoS One 2012, 7, e31901.
[45]
Li, S.S.-L.; Liu, Y.H.; Tseng, C.N.; Chung, T.L.; Lee, T.Y.; Singh, S. Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan. Stem Cells Dev 2006, 15, 532–555.
[46]
Chen, B.Z.; Yu, S.L.; Singh, S.; Kao, L.P.; Tsai, Z.Y.; Yang, P.C.; Chen, B.H.; Li, S.S.-L. Identification of microRNAs expressed highly in pancreatic islet-like cell clusters differentiated from human embryonic stem cells. Cell Biol. Int 2011, 35, 29–37.
