Abstract
Endocrine disrupting chemicals that are structurally similar to steroid or amine hormones have the potential to mimic endocrine endpoints at the receptor level. Endocrine disrupting chemicals may dysregulate hormone-mediated gene expression through changes in signal transduction and through epigenetic changes. However, epigenetic-induced alteration in gene expression may occur outside of receptor-mediated effects and has emerged as an alternative way in which environmental compounds may exert endocrine effects. We discuss general implications of DNA methylation, histone modification, micro RNAs, and other more recently recognized epigenetic modifications for endocrinology, and we discuss potential for transgenerational inheritance of epigenetic marks. We also review concepts related to environmental epigenetics and relevance for endocrinology through three broad examples, (1) effect of prenatal and early-life under- and overnutrition on future metabolic disease, (2) effect of lifetime environmental exposures such as ionizing radiation on endocrine cancer risk, and (3) potential for compounds previously classified as endocrine disrupting to additionally or alternatively exert effects through epigenetic mechanisms. The field of environmental epigenetics is still nascent, and additional studies are needed to confirm and reinforce data derived from animal models and preliminary human studies. Current evidence suggests that environmental exposures may significantly impact expression of endocrine-related genes and thereby affect clinical endocrine outcomes.
This chapter is adapted from Bioscientifica: Journal of Molecular Endocrinology. Fleisch AF, Wright RO, Baccarelli AA (2012) Environmental epigenetics: a role in endocrine disease? 49(2):R61–67.
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References
Alegria-Torres JA, Baccarelli A, Bollati V (2011) Epigenetics and lifestyle. Epigenomics 3:267–277
Anway MD, Cupp AS, Uzumcu M, Skinner MK (2005) Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308:1466–1469
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Bennett KL, Lee W, Lamarre E, Zhang X, Seth R, Scharpf J et al (2010) HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas. Genes Chromosomes Cancer 49:319–326
Bird AP, Wolffe AP (1999) Methylation-induced repression–belts, braces, and chromatin. Cell 99:451–454
Bird MG, Greim H, Snyder R, Rice JM (2005) International symposium: recent advances in benzene toxicity. Chem Biol Interact 153–154:1–5
Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H et al (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883
Boeke CE, Baccarelli A, Kleinman KP, Burris HH, Litonjua AA, Rifas-Shiman SL et al (2012) Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population. Epigenetics 7:253–260
Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D et al (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67:876–880
Booth MJ, Branco MR, Ficz G, Oxley D, Krueger F, Reik W et al (2012) Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336:934–937
Bruner-Tran KL, Osteen KG (2011) Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reprod Toxicol 31:344–350
Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA (2007) 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. Br J Nutr 97:435–439
Byun HM, Panni T, Motta V, Hou L, Nordio F, Apostoli P et al (2013) Effects of airborne pollutants on mitochondrial DNA methylation. Part Fibre Toxicol 10:18
Caudill CM, Zhu Z, Ciampi R, Stringer JR, Nikiforov YE (2005) Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation. J Clin Endocrinol Metab 90:2364–2369
Chen K, Rajewsky N (2007) The evolution of gene regulation by transcription factors and microRNAs. Nat Rev Genet 8:93–103
Christodouleas JP, Forrest RD, Ainsley CG, Tochner Z, Hahn SM, Glatstein E (2011) Short-term and long-term health risks of nuclear-power-plant accidents. N Engl J Med 364:2334–2341
Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A et al (2011) Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146:67–79
Dawid IB (1974) 5-methylcytidylic acid: absence from mitochondrial DNA of frogs and HeLa cells. Science 184:80–81
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC, Hauser R, Prins GS, Soto AM et al (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 30:293–342
Doi A, Park IH, Wen B, Murakami P, Aryee MJ, Irizarry R et al (2009) Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat Genet 41:1350–1353
Dolinoy DC (2008) The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome. Nutr Rev 66(Suppl 1):S7–S11
Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, Nicholson GC et al (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7:e1001372
Erhuma A, Salter AM, Sculley DV, Langley-Evans SC, Bennett AJ (2007) Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol Endocrinol Metab 292:E1702–E1714
Falck L, Forsberg JG (1996) Immunohistochemical studies on the expression and estrogen dependency of EGF and its receptor and C-fos proto-oncogene in the uterus and vagina of normal and neonatally estrogen-treated mice. Anat Rec 245:459–471
Figueroa ME, Skrabanek L, Li Y, Jiemjit A, Fandy TE, Paietta E et al (2009) MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood 114:3448–3458
Fleisch AF, Sheffield PE, Chinn C, Edelstein BL, Landrigan PJ (2010) Bisphenol A and related compounds in dental materials. Pediatrics 126:760–768
Fleischman A, Kron M, Systrom DM, Hrovat M, Grinspoon SK (2009) Mitochondrial function and insulin resistance in overweight and normal-weight children. J Clin Endocrinol Metab 94:4923–4930
Fryer AA, Nafee TM, Ismail KM, Carroll WD, Emes RD, Farrell WE (2009) LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: a preliminary study. Epigenetics 4:394–398
Giotopoulos G, McCormick C, Cole C, Zanker A, Jawad M, Brown R et al (2006) DNA methylation during mouse hemopoietic differentiation and radiation-induced leukemia. Exp Hematol 34:1462–1470
Godfrey KM, Sheppard A, Gluckman PD, Lillycrop KA, Burdge GC, McLean C et al (2011) Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 60:1528–1534
Guenard F, Deshaies Y, Cianflone K, Kral JG, Marceau P, Vohl MC (2013) Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery. Proc Natl Acad Sci U S A 110:11439–11444
Hayward BE, Barlier A, Korbonits M, Grossman AB, Jacquet P, Enjalbert A et al (2001) Imprinting of the G(s)alpha gene GNAS1 in the pathogenesis of acromegaly. J Clin Invest 107:R31–R36
He L, Hannon GJ (2004) MicroRNAs: small RNAs with a big role in gene regulation. Nat Genet Rev 5:522–531
He C, Kraft P, Chen C, Buring JE, Pare G, Hankinson SE et al (2009) Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 41:724–728
Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES et al (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A 105:17046–17049
Hobert JA, Eng C (2009) PTEN hamartoma tumor syndrome: an overview. Genet Med 11:687–694
Hypponen E, Smith GD, Power C (2003) Parental diabetes and birth weight of offspring: intergenerational cohort study. BMJ 326:19–20
Inawaka K, Kawabe M, Takahashi S, Doi Y, Tomigahara Y, Tarui H et al (2009) Maternal exposure to anti-androgenic compounds, vinclozolin, flutamide and procymidone, has no effects on spermatogenesis and DNA methylation in male rats of subsequent generations. Toxicol Appl Pharmacol 237:178–187
Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303
Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8:253–262
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N et al (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191
Kile ML, Baccarelli A, Tarantini L, Hoffman E, Wright RO, Christiani DC (2010) Correlation of global and gene-specific DNA methylation in maternal-infant pairs. PLoS One 5:e13730
Kujjo LL, Chang EA, Pereira RJ, Dhar S, Marrero-Rosado B, Sengupta S et al (2011) Chemotherapy-induced late transgenerational effects in mice. PLoS One 6:e17877
Langley-Evans SC (2009) Nutritional programming of disease: unravelling the mechanism. J Anat 215:36–51
Law CM, Barker DJ, Osmond C, Fall CH, Simmonds SJ (1992) Early growth and abdominal fatness in adult life. J Epidemiol Community Health 46:184–186
Le HH, Carlson EM, Chua JP, Belcher SM (2008) Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol Lett 176:149–156
Li S, Washburn KA, Moore R, Uno T, Teng C, Newbold RR et al (1997) Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res 57:4356–4359
Li CC, Young PE, Maloney CA, Eaton SA, Cowley MJ, Buckland ME et al (2013) Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic mice. Epigenetics 8:602–611
Lillycrop KA (2011) Effect of maternal diet on the epigenome: implications for human metabolic disease. Proc Nutr Soc 70:64–72
Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386
Lindgren CM, Heid IM, Randall JC, Lamina C, Steinthorsdottir V, Qi L et al (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508
Lindsay RS, Dabelea D, Roumain J, Hanson RL, Bennett PH, Knowler WC (2000) Type 2 diabetes and low birth weight: the role of paternal inheritance in the association of low birth weight and diabetes. Diabetes 49:445–449
Mantovani G, Lania AG, Spada A (2010) GNAS imprinting and pituitary tumors. Mol Cell Endocrinol 326:15–18
Mathers JC, Strathdee G, Relton CL (2010) Induction of epigenetic alterations by dietary and other environmental factors. Adv Genet 71:3–39
McCormack SE, McCarthy MA, Farilla L, Hrovat MI, Systrom DM, Grinspoon SK et al (2011) Skeletal muscle mitochondrial function is associated with longitudinal growth velocity in children and adolescents. J Clin Endocrinol Metab 96:E1612–E1618
Nam SH, Seo YM, Kim MG (2010) Bisphenol A migration from polycarbonate baby bottle with repeated use. Chemosphere 79:949–952
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389
Nelson KG, Sakai Y, Eitzman B, Steed T, McLachlan J (1994) Exposure to diethylstilbestrol during a critical developmental period of the mouse reproductive tract leads to persistent induction of two estrogen-regulated genes. Cell Growth Differ 5:595–606
Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467:963–966
Orphanides G, Reinberg D (2002) A unified theory of gene expression. Cell 108:439–451
Painter RC, Roseboom TJ, Bleker OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reprod Toxicol 20:345–352
Park BH, Kim YJ, Park JS, Lee HY, Ha EH, Min JW et al (2005) Folate and homocysteine levels during pregnancy affect DNA methylation in human placenta. J Prev Med Public Health 38:437–442
Pentinat T, Ramon-Krauel M, Cebria J, Diaz R, Jimenez-Chillaron JC (2010) Transgenerational inheritance of glucose intolerance in a mouse model of neonatal overnutrition. Endocrinology 151:5617–5623
Perera F, Herbstman J (2011) Prenatal environmental exposures, epigenetics, and disease. Reprod Toxicol 31:363–373
Perry JR, Stolk L, Franceschini N, Lunetta KL, Zhai G, McArdle PF et al (2009) Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat Genet 41:648–650
Plagemann A, Harder T, Brunn M, Harder A, Roepke K, Wittrock-Staar M et al (2009) Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 587:4963–4976
Plagemann A, Roepke K, Harder T, Brunn M, Harder A, Wittrock-Staar M et al (2010) Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding. J Perinat Med 38:393–400
Raiber EA, Beraldi D, Ficz G, Burgess HE, Branco MR, Murat P et al (2012) Genome-wide distribution of 5-formylcytosine in embryonic stem cells is associated with transcription and depends on thymine DNA glycosylase. Genome Biol 13:R69
Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093
Robboy SJ, Scully RE, Welch WR, Herbst AL (1977) Intrauterine diethylstilbestrol exposure and its consequences: pathologic characteristics of vaginal adenosis, clear cell adenocarcinoma, and related lesions. Arch Pathol Lab Med 101:1–5
Robertson KD, Wolffe AP (2000) DNA methylation in health and disease. Nat Genet Rev 1:11–19
Romao JM, Jin W, Dodson MV, Hausman GJ, Moore SS, Guan LL (2011) MicroRNA regulation in mammalian adipogenesis. Exp Biol Med (Maywood) 236:997–1004
Rusiecki JA, Baccarelli A, Bollati V, Tarantini L, Moore LE, Bonefeld-Jorgensen EC (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect 116:1547–1552
Russo D, Damante G, Puxeddu E, Durante C, Filetti S (2011) Epigenetics of thyroid cancer and novel therapeutic targets. J Mol Endocrinol 46:R73–R81
Schafer SA, Machicao F, Fritsche A, Haring HU, Kantartzis K (2011) New type 2 diabetes risk genes provide new insights in insulin secretion mechanisms. Diabetes Res Clin Pract 93(Suppl 1):S9–S24
Schneider S, Kaufmann W, Buesen R, van Ravenzwaay B (2008) Vinclozolin–the lack of a transgenerational effect after oral maternal exposure during organogenesis. Reprod Toxicol 25:352–360
Shi L, Wu J (2009) Epigenetic regulation in mammalian preimplantation embryo development. Reprod Biol Endocrinol 7:59
Shock LS, Thakkar PV, Peterson EJ, Moran RG, Taylor SM (2011) DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci U S A 108:3630–3635
Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J et al (2007) DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A 104:19351–19356
Skinner MK (2008) What is an epigenetic transgenerational phenotype? F3 or F2. Reprod Toxicol 25:2–6
Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X et al (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68–72
Steegers-Theunissen RP, Obermann-Borst SA, Kremer D, Lindemans J, Siebel C, Steegers EA et al (2009) Periconceptional maternal folic acid use of 400 microg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 4:e7845
Stocker CJ, Arch JR, Cawthorne MA (2005) Fetal origins of insulin resistance and obesity. Proc Nutr Soc 64:143–151
Stouder C, Paoloni-Giacobino A (2010) Transgenerational effects of the endocrine disruptor vinclozolin on the methylation pattern of imprinted genes in the mouse sperm. Reproduction 139:373–379
Tamminga J, Koturbash I, Baker M, Kutanzi K, Kathiria P, Pogribny IP et al (2008) Paternal cranial irradiation induces distant bystander DNA damage in the germline and leads to epigenetic alterations in the offspring. Cell Cycle 7:1238–1245
Thomson JP, Hunter JM, Lempiainen H, Muller A, Terranova R, Moggs JG et al (2013) Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver. Nucleic Acids Res 41:5639–5654
van Kaam KJ, Delvoux B, Romano A, D’Hooghe T, Dunselman GA, Groothuis PG (2011) Deoxyribonucleic acid methyltransferases and methyl-CpG-binding domain proteins in human endometrium and endometriosis. Fertil Steril 95:1421–1427
Vandeva S, Jaffrain-Rea ML, Daly AF, Tichomirowa M, Zacharieva S, Beckers A (2010) The genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 24:461–476
Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589
Waddington C (1942) The epigenome. Endeavour 1:18–20
Wolff GL, Kodell RL, Moore SR, Cooney CA (1998) Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12:949–957
Wolffe AP, Guschin D (2000) Review: chromatin structural features and targets that regulate transcription. J Struct Biol 129:102–122
Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286:481–486
Yan C, Boyd DD (2006) Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression. Mol Cell Biol 26:6357–6371
Zhu H, Shyh-Chang N, Segre AV, Shinoda G, Shah SP, Einhorn WS et al (2011) The Lin28/let-7 axis regulates glucose metabolism. Cell 147:81–94
Declaration of Interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
The authors have received support from the following grants from the US National Institutes of Health: P30ES000002, R21ES019773, R21ES020010, R01ES020268, R01ES013744, R01ES014930, R01ES021357, P42ES016454, and K12 DK094721-02; from the Agency of Healthcare Research and Quality: T32 HS00063; and from Harvard School of Public Health.
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Fleisch, A.F., Wright, R.O., Baccarelli, A.A. (2015). Is Environmental Epigenetics Relevant to Endocrine Disease?. In: Su, L., Chiang, Tc. (eds) Environmental Epigenetics. Molecular and Integrative Toxicology. Springer, London. https://doi.org/10.1007/978-1-4471-6678-8_4
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