Epigenetic reprogramming and imprinting in origins of disease

  • Wan-yee Tang
  • Shuk-mei HoEmail author


The traditional view that gene and environment interactions control disease susceptibility can now be expanded to include epigenetic reprogramming as a key determinant of origins of human disease. Currently, epigenetics is defined as heritable changes in gene expression that do not alter DNA sequence but are mitotically and transgenerationally inheritable. Epigenetic reprogramming is the process by which an organism’s genotype interacts with the environment to produce its phenotype and provides a framework for explaining individual variations and the uniqueness of cells, tissues, or organs despite identical genetic information. The main epigenetic mediators are histone modification, DNA methylation, and non-coding RNAs. They regulate crucial cellular functions such as genome stability, X-chromosome inactivation, gene imprinting, and reprogramming of non-imprinting genes, and work on developmental plasticity such that exposures to endogenous or exogenous factors during critical periods permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish “adaptive” phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, medical interventions, environmental pollutants, and lifestyle choices, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases. The recent identification of a significant number of epigenetically regulated genes in various model systems has prepared the field to take on the challenge of characterizing distinct epigenomes related to various diseases. Improvements in human health could then be redirected from curative care to personalized, preventive medicine based, in part, on epigenetic markings etched in the “margins” of one’s genetic make-up.


DNA methylation Histone modification Chromatin remodeling Nongenomic heritage Developmental plasticity Relaxation of imprinting 



Grant support: NIH grants to S-M Ho: ES12281, ES13071, ES15905, and ES15584 and the Department of Defense award to W-Y Tang: DAMD W81XWH-06-1-0373 (W-Y Tang).


  1. 1.
    Liu Y, Freedman BI. Genetics of progressive renal failure in diabetic kidney disease. Kidney Int 2005;Suppl S94–7.Google Scholar
  2. 2.
    Kroll TG. Molecular events in follicular thyroid tumors. Cancer Treat Res 2004;122:85–105.PubMedCrossRefGoogle Scholar
  3. 3.
    Moore MA. Converging pathways in leukemogenesis and stem cell self-renewal. Exp Hematol 2005;33:719–37.PubMedCrossRefGoogle Scholar
  4. 4.
    Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol 2005;23:8253–61.PubMedCrossRefGoogle Scholar
  5. 5.
    Tusie Luna MT. Genes and type 2 diabetes mellitus. Arch Med Res 2005;36:210–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Soussi T, Ishioka C, Claustres M, Beroud C. Locus-specific mutation databases: pitfalls and good practice based on the p53 experience. Nat Rev Cancer 2006;6:83–90.PubMedCrossRefGoogle Scholar
  7. 7.
    Garg V. Insights into the genetic basis of congenital heart disease. Cell Mol Life Sci 2006;63;1141–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Godfrey KM, Lillycrop KA, Burdge GC, Gluckman PD, Hanson MA. Epigenetic mechanisms and the mismatch concept of the developmental origins of health and disease. Pediatr Res 2007;61:5R–10R.PubMedCrossRefGoogle Scholar
  9. 9.
    Jiang YH, Bressler J, Beaudet AL. Epigenetics and human disease. Annu Rev Genomics Hum Genet 2004;5:479–510.PubMedCrossRefGoogle Scholar
  10. 10.
    Dolinoy DC, Weidman JR, Jirtle RL. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol 2007;23:297–307.PubMedCrossRefGoogle Scholar
  11. 11.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003;33 Suppl:245–54.PubMedCrossRefGoogle Scholar
  12. 12.
    Van Speybroeck L. From epigenesis to epigenetics: the case of C. H. Waddington. Ann NY Acad Sci 2002;981:61–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Waddington CH. The stragegy of the genes: a discussion of some aspects of theoretical biology. New York: Macmillan;1957.Google Scholar
  14. 14.
    Akhtar A, Cavalli G. The epigenome network of excellence. PLoS Biol 2005;3:e177.PubMedCrossRefGoogle Scholar
  15. 15.
    Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E. Metastable epialleles in mammals. Trends Genet 2002;18:348–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KV, Whitelaw E. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003;100:2538–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308:1466–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Morris KV. siRNA-mediated transcriptional gene silencing: the potential mechanism and a possible role in the histone code. Cell Mol Life Sci 2005;62:3057–66.PubMedCrossRefGoogle Scholar
  19. 19.
    Cheung P, Lau P. Epigenetic regulation by histone methylation and histone variants. Mol Endocrinol 2005;19:563–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Esteller M. Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 2005;45:629–56.PubMedCrossRefGoogle Scholar
  21. 21.
    Holliday R. Mutations and epimutations in mammalian cells. Mutat Res 1991;250:351–63.PubMedGoogle Scholar
  22. 22.
    Fernandez-Twinn DS, Ozanne SE. Mechanisms by which poor early growth programs type-2 diabetes, obesity and the metabolic syndrome. Physiol Behav 2006;88:234–43.PubMedCrossRefGoogle Scholar
  23. 23.
    Barker DJ, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 1993;306:422–6.PubMedGoogle Scholar
  24. 24.
    Gluckman PD, Hanson MA. The developmental origins of the metabolic syndrome. Trends Endocrinol Metab 2004;15:183–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Ravelli AC, Van Der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998;351:173–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Dennison EM, Arden NK, Keen RW, Syddall H, Day IN, Spector TD, Cooper C. Birthweight, vitamin D receptor genotype and the programming of osteoporosis. Paediatr Perinat Epidemiol 2001;15:211–9.Google Scholar
  27. 27.
    Thompson C, Syddall H, Rodin I, Osmond C, Barker DJ. Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 2001;179:450–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Lahr MM, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE. Developmental plasticity and human health. Nature 2004;430:419–21.PubMedCrossRefGoogle Scholar
  29. 29.
    Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science 2004;305:1733–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006;7:437–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Singal R, Ginder GD. DNA methylation. Blood 1999;93:4059–70.PubMedGoogle Scholar
  32. 32.
    Dolinoy DC, Das R, Weidman JR, Jirtle RL. Metastable epialleles, imprinting, and the fetal origins of adult diseases. Pediatr Res 2007;61:30R–7R.PubMedCrossRefGoogle Scholar
  33. 33.
    Verdel A, Jia S, Gerber S, Sugiyama T, Gygi S, Grewal SI, Moazed D. RNAi-mediated targeting of heterochromatin by the RITS complex. Science 2004;303:672–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Matzke MA, Birchler JA. RNAi-mediated pathways in the nucleus. Nat Rev Genet 2005;6:24–35.PubMedCrossRefGoogle Scholar
  35. 35.
    Costello JF, Plass C. Methylation matters. J Med Genet 2001;38:285–303.PubMedCrossRefGoogle Scholar
  36. 36.
    Antequera F, Bird A. Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci USA 1993;90:11995–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Murphy SK, Jirtle RL. Imprinted genes as potential genetic and epigenetic toxicologic targets. Environ Health Perspect 2000;108 Suppl 1:5–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Monk M, Boubelik M, Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 1987;99:371–82.PubMedGoogle Scholar
  39. 39.
    Kafri T, Ariel M, Brandeis M, Shemer R, Urven L, McCarrey J, Cedar H, Razin A. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. Genes Dev 1992;6:705–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Issa JP. CpG-island methylation in aging and cancer. Curr Top Microbiol Immunol 2000;249:101–18.PubMedGoogle Scholar
  41. 41.
    Ho SM, Tang WY. Techniques used in studies of epigenome dysregulation due to aberrant DNA methylation: an emphasis on fetal-based adult diseases. Reprod Toxicol 2007;23:267–82.PubMedCrossRefGoogle Scholar
  42. 42.
    Jenuwein T, Allis CD. Translating the histone code. Science 2001;293:1074–80.PubMedCrossRefGoogle Scholar
  43. 43.
    Crews D, McLachlan JA. Epigenetics, evolution, endocrine disruption, health, and disease. Endocrinology 2006;147:S4–10.PubMedCrossRefGoogle Scholar
  44. 44.
    Gatz M, Prescott CA, Pedersen NL. Lifestyle risk and delaying factors. Alzheimer Dis Assoc Disord 2006;20:S84–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Heindel JJ. Role of exposure to environmental chemicals in the developmental basis of reproductive disease and dysfunction. Semin Reprod Med 2006;24:168–77.PubMedCrossRefGoogle Scholar
  46. 46.
    Hilakivi-Clarke L, De Assis S. Fetal origins of breast cancer. Trends Endocrinol Metab 2006;17:340–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Phillips DI. Programming of the stress response: a fundamental mechanism underlying the long-term effects of the fetal environment? J Intern Med 2007;261:453–60.PubMedCrossRefGoogle Scholar
  48. 48.
    Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 2003;23:5293–300.PubMedCrossRefGoogle Scholar
  49. 49.
    Waterland RA, Dolinoy DC, Lin JR, Smith CA, Shi X, Tahiliani KG. Maternal methyl supplements increase offspring DNA methylation at Axin Fused. Genesis 2006:44:401–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Castro R, Rivera I, Struys EA, Jansen EE, Ravasco P, Camilo ME, Blom HJ, Jakobs C, Tavares dA I. Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin Chem 2003;49:1292–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Friso S, Choi SW, Dolnikowski GG, Selhub J. A method to assess genomic DNA methylation using high-performance liquid chromatography/electrospray ionization mass spectrometry. Anal Chem 2002;74:4526–31.PubMedCrossRefGoogle Scholar
  52. 52.
    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. Mech Ageing Dev 1998;106:93–102.PubMedCrossRefGoogle Scholar
  53. 53.
    Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208–11.PubMedCrossRefGoogle Scholar
  54. 54.
    Yokomori N, Tawata M, Onaya T. DNA demethylation during the differentiation of 3T3-L1 cells affects the expression of the mouse GLUT4 gene. Diabetes 1999;48:685–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Carretero MV, Torres L, Latasa U, Garcia-Trevijano ER, Prieto J, Mato JM, Avila MA. Transformed but not normal hepatocytes express UCP2. FEBS Lett 1998;439:55–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Lamartiniere CA, Cotroneo MS, Fritz WA, Wang J, Mentor-Marcel R, Elgavish A. Genistein chemoprevention: timing and mechanisms of action in murine mammary and prostate. J Nutr 2002;132:552S–8S.PubMedGoogle Scholar
  57. 57.
    Valachovicova T, Slivova V, Bergman H, Shuherk J, Sliva D. Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition of NF-kappaB/AP-1-dependent and -independent pathways. Int J Oncol 2004;25:1389–95.PubMedGoogle Scholar
  58. 58.
    Lyn-Cook BD, Blann E, Payne PW, Bo J, Sheehan D, Medlock K. Methylation profile and amplification of proto-oncogenes in rat pancreas induced with phytoestrogens. Proc Soc Exp Biol Med 1995;208:116–9.PubMedGoogle Scholar
  59. 59.
    Day JK, Bauer AM, DesBordes C, Zhuang Y, Kim BE, Newton LG, Nehra V, Forsee KM, MacDonald RS, Besch-Williford C, Huang TH, Lubahn DB. Genistein alters methylation patterns in mice. J Nutr 2002;132:2419S–23S.PubMedGoogle Scholar
  60. 60.
    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. Environ Health Perspect 2006;114:567–72.PubMedCrossRefGoogle Scholar
  61. 61.
    Jefferson WN, Padilla-Banks E, Newbold RR. Disruption of the female reproductive system by the phytoestrogen genistein. Reprod Toxicol 2007;23:308–16.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol 2005;68:1018–30.PubMedCrossRefGoogle Scholar
  63. 63.
    Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res 2003;63:7563–70.PubMedGoogle Scholar
  64. 64.
    Cheng RY, Hockman T, Crawford E, Anderson LM, Shiao YH. Epigenetic and gene expression changes related to transgenerational carcinogenesis. Mol Carcinog 2004;40:1–11.PubMedCrossRefGoogle Scholar
  65. 65.
    Shiao YH, Crawford EB, Anderson LM, Patel P, Ko K. Allele-specific germ cell epimutation in the spacer promoter of the 45S ribosomal RNA gene after Cr(III) exposure. Toxicol Appl Pharmacol 2005;205:290–96.PubMedCrossRefGoogle Scholar
  66. 66.
    Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 2003;286:355–65.PubMedCrossRefGoogle Scholar
  67. 67.
    Poirier LA, Vlasova TI. The prospective role of abnormal methyl metabolism in cadmium toxicity. Environ Health Perspect 2002;110 Suppl 5:793–5.PubMedGoogle Scholar
  68. 68.
    Waalkes MP, Liu J, Ward JM, Diwan BA. Mechanisms underlying arsenic carcinogenesis: hypersensitivity of mice exposed to inorganic arsenic during gestation. Toxicology 2004;198:31–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Waalkes MP, Ward JM, Diwan BA. Induction of tumors of the liver, lung, ovary and adrenal in adult mice after brief maternal gestational exposure to inorganic arsenic: promotional effects of postnatal phorbol ester exposure on hepatic and pulmonary, but not dermal cancers. Carcinogenesis 2004;25:133–41.PubMedCrossRefGoogle Scholar
  70. 70.
    Reichard JF, Schnekenburger M, Puga A. Long term low-dose arsenic exposure induces loss of DNA methylation. Biochem Biophys Res Commun 2007;352:188–92.PubMedCrossRefGoogle Scholar
  71. 71.
    Silbergeld EK, Waalkes M, Rice JM. Lead as a carcinogen: experimental evidence and mechanisms of action. Am J Ind Med 2000;38:316–23.PubMedCrossRefGoogle Scholar
  72. 72.
    Salnikow K, Costa M. Epigenetic mechanisms of nickel carcinogenesis. J Environ Pathol Toxicol Oncol 2000;19:307–18.PubMedGoogle Scholar
  73. 73.
    Chen H, Ke Q, Kluz T, Yan Y, Costa M. Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol Cell Biol 2006;26:3728–37.PubMedCrossRefGoogle Scholar
  74. 74.
    Veurink M, Koster M, Berg LT. The history of DES, lessons to be learned. Pharm World Sci 2005;27:139–43.PubMedCrossRefGoogle Scholar
  75. 75.
    Li S, Washburn KA, Moore R, Uno T, Teng C, Newbold RR, McLachlan JA, Negishi M. Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res 1997;57:4356–9.PubMedGoogle Scholar
  76. 76.
    Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC. Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 2003;38:78–84.PubMedCrossRefGoogle Scholar
  77. 77.
    Alworth LC, Howdeshell KL, Ruhlen RL, Day JK, Lubahn DB, Huang TH, Besch-Williford CL, vom Saal FS. 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. Toxicol Appl Pharmacol 2002;183:10–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Sato K, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice. Endocr J 2006;53:331–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Tang W, Barker J, Jefferson WN, Newbold RR, Ho S. Early exposure to diethylstilbestrol or genistein and uterine cancer risk: investigating nucleosomal binding protein 1 (Nsbp1) as a gene susceptible to estrogen reprogramming in the mouse uterus. Endocrine Society’s 89th Annual Meeting Proceeding. p95, 2007.Google Scholar
  80. 80.
    Newbold RR, Padilla-Banks E, Jefferson WN. Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations. Endocrinology 2006;147:S11–7.PubMedCrossRefGoogle Scholar
  81. 81.
    Ruden DM, Xiao L, Garfinkel MD, Lu X. Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Hum Mol Genet 2005;14 Spec No. 1:R149–55.PubMedCrossRefGoogle Scholar
  82. 82.
    Maffini MV, Rubin BS, Sonnenschein C, Soto AM. Endocrine disruptors and reproductive health: the case of bisphenol-A. Mol Cell Endocrinol 2006;254–255:179–86.PubMedCrossRefGoogle Scholar
  83. 83.
    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:S56–69.PubMedCrossRefGoogle Scholar
  84. 84.
    Ho SM, Tang WY, Belmonte dF, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 2006;66:5624–32.PubMedCrossRefGoogle Scholar
  85. 85.
    Anway MD, Leathers C, Skinner MK. Endocrine disruptor vinclozolin induced epigenetic transgenerational adult onset disease. Endocrinology 2006;147:5515–23.PubMedCrossRefGoogle Scholar
  86. 86.
    Crews D, Gore AC, Hsu TS, Dangleben NL, Spinetta M, Schallert T, Anway MD, Skinner MK. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA 2007;104:5942–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Couture LA, Abbott BD, Birnbaum LS. A critical review of the developmental toxicity and teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: recent advances toward understanding the mechanism. Teratology 1990;42:619–27.PubMedCrossRefGoogle Scholar
  88. 88.
    Wu Q, Ohsako S, Ishimura R, Suzuki JS, Tohyama C. Exposure of mouse preimplantation embryos to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters the methylation status of imprinted genes H19 and Igf2. Biol Reprod 2004;70:1790–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Bradley C, van der MR, Roodi N, Yan H, Chandrasekharan MB, Sun ZW, Mernaugh RL, Parl FF. Carcinogen-induced histone alteration in normal human mammary epithelial cells carcinogenesis, 2007.Google Scholar
  90. 90.
    Foster PM. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int J Androl 2006;29:140–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Desaulniers D, Xiao GH, Leingartner K, Chu I, Musicki B, Tsang BK. Comparisons of brain, uterus, and liver mRNA expression for cytochrome p450s, DNA methyltransferase-1, and catechol-o-methyltransferase in prepubertal female Sprague–Dawley rats exposed to a mixture of aryl hydrocarbon receptor agonists. Toxicol Sci 2005;86:175–84.CrossRefGoogle Scholar
  92. 92.
    McLachlan JA, Simpson E, Martin M. Endocrine disrupters and female reproductive health. Best Pract Res Clin Endocrino Metab 2006;20:63–75.PubMedCrossRefGoogle Scholar
  93. 93.
    Tao L, Wang W, Li L, Kramer PK, Pereira MA. DNA hypomethylation induced by drinking water disinfection by-products in mouse and rat kidney. Toxicol Sci 2005;87:344–52.PubMedCrossRefGoogle Scholar
  94. 94.
    Prins GS, Birch L, Tang WY, Ho SM. Developmental estrogen exposures predispose to prostate carcinogenesis with aging. Reprod Toxicol 2007;23:374–82.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of Environmental Health, College of MedicineUniversity of CincinnatiCincinnatiUSA
  2. 2.Department of Environmental Health and Cancer Center, College of MedicineUniversity of CincinnatiCincinnatiUSA

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