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Identification of Uterine Leiomyoma Genes Developmentally Reprogrammed by Neonatal Exposure to Diethylstilbestrol

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Abstract

Environmental exposures during development can alter susceptibility later in life to adult diseases including uterine leiomyoma, a phenomenon termed developmental reprogramming. The goal of this study was to identify genes developmentally reprogrammed by diethylstilbestrol (DES) and aberrantly expressed in leiomyomas. Transcriptional profiling identified 171 genes differentially expressed in leiomyomas relative to normal myometrium, of which 6/18 genes with putative estrogen responsive elements and confirmed to be estrogen-responsive in neonatal uteri were reprogrammed by neonatal DES exposure. Calbindin D9k and Dio2, normally induced by estrogen, exhibited elevated expression in DES-exposed animals during both phases of the estrus cycle. Gdf10, Car8, Gria2, and Mmp3, genes normally repressed by estrogen, exhibited elevated expression in DES-exposed animals during the proliferative phase, when estrogen is highest. These data demonstrate that neonatal DES exposure causes reprogramming of estrogen-responsive genes expressed in uterine leiomyomas, leading to over-expression of these genes in the myometrium of exposed animals prior to the onset of tumorigenesis.

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References

  1. Gluckman PD, Hanson MA Developmental plasticity and human disease: research directions. J Intern Med. 2007;261: 461–471.

    Article  CAS  PubMed  Google Scholar 

  2. Smith-Gill SJ Developmental plasticity: developmental conversion versus phenotypic modulation. Am Zool. 1983;1:47–55.

    Article  Google Scholar 

  3. Bateson P., Barker D., Clutton-Brock T., et al. Developmental plasticity and human health. Nature. 2004;430:419–421.

    Article  CAS  PubMed  Google Scholar 

  4. Birnbaum LS, Fenton SE Cancer and developmental exposure to endocrine disruptors. Environ Health Perspect. 2003;111:389–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kyung-Chul C., Eui-Bae J., Leung PCK. Impact of environmental endocrine disruption on the reproductive system for human health. Immunol, Endocr & Metab Agents-Med Chem. 2006;6:3–13.

    Google Scholar 

  6. McLachlan JA, Newbold RR, Shah HC, Hogan MD, Dixon RL Reduced fertility in female mice exposed transplacentally to diethylstilbestrol (DES). Fertil Steril. 1982;38:364–371.

    Article  CAS  PubMed  Google Scholar 

  7. Miller KP, Borgeest C., Greenfeld C., Tomic D., Flaws JA In utero effects of chemicals on reproductive tissues in females. Toxicol Appl Pharmacol. 2004;198:111–131.

    Article  CAS  PubMed  Google Scholar 

  8. Newbold RR, Banks EP, Bullock B., Jefferson WN Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res. 2001;61:4325–4328.

    CAS  PubMed  Google Scholar 

  9. Palmer JR, Wise LA, Hatch EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1509–1514.

    Article  CAS  PubMed  Google Scholar 

  10. Herbst AL, Scully RE Adenocarcinoma of the vagina in adolescence. A report of 7 cases including 6 clear-cell carcinomas (so-called mesonephromas). Cancer. 1970;25:745–757.

    Article  CAS  PubMed  Google Scholar 

  11. Herbst AL, Cole P., Colton T., Robboy SJ, Scully RE Age-incidence and risk of diethylstilbestrol-related clear cell adenocarcinoma of the vagina and cervix. Am J Obstet Gynecol. 1977;128:43–50.

    Article  CAS  PubMed  Google Scholar 

  12. Herbst AL, Ulfelder H., Poskanzer DC Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878–881.

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman RH Structural changes of the genital tract associated with in utero exposure to diethylstilbestrol. Obstet Gynecol Annu. 1982;11:187–202.

    CAS  PubMed  Google Scholar 

  14. Goldberg JM, Falcone T. Effect of diethylstilbestrol on reproductive function. Fertil Steril. 1999;72:1–7.

    Article  CAS  PubMed  Google Scholar 

  15. Hatch EE, Troisi R., Wise LA, et al. Age at natural menopause in women exposed to diethylstilbestrol in utero. Am J Epidemiol. 2006;164:682–688.

    Article  PubMed  Google Scholar 

  16. Baird DD, Newbold R. Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reprod Toxicol. 2005;20:81.

    Article  CAS  PubMed  Google Scholar 

  17. Troisi R., Titus-Ernstoff L., Hyer M., et al. Preeclampsia risk in women exposed in utero to diethylstilbestrol. Obstet Gynecol. 2007;110:113–120.

    Article  PubMed  Google Scholar 

  18. Walker CL, Stewart EA Uterine fibroids: the elephant in the room. Science. 2005;308:1589–1592.

    Article  CAS  PubMed  Google Scholar 

  19. Cook JD, Davis BJ, Cai SL, Barrett JC, Conti CJ, Walker CL Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance. Proc Natl Acad Sci U S A. 2005;102:8644–8649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cook JD, Davis BJ, Goewey JA, Berry TD, Walker CL Identification of a sensitive period for developmental programming that increases risk for uterine leiomyoma in eker rats. Reprod Sci. 2007;14:121–136.

    Article  PubMed  Google Scholar 

  21. Newbold RR, Moore AB, Dixon D. Characterization of uterine leiomyomas in CD-1 mice following developmental exposure to diethylstilbestrol (DES). Toxicol Pathol. 2002; 30:611–616.

    Article  CAS  PubMed  Google Scholar 

  22. Zheng X., Hendry WJ, 3rdNeonatal diethylstilbestrol treatment alters the estrogen-regulated expression of both cell proliferation and apoptosis-related proto-oncogenes (c-jun, c-fos, c-myc, bax, bcl-2, and bcl-x) in the hamster uterus. Cell Growth Differ. 1997;8:425–434.

    CAS  PubMed  Google Scholar 

  23. Nelson KG, Sakai Y., Eitzman B., Steed T., McLachlan J. 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. 1994;5:595–606.

    CAS  PubMed  Google Scholar 

  24. Mo R., Tony Zhu Y., Zhang Z., Rao SM, Zhu YJ GAS6 is an estrogen-inducible gene in mammary epithelial cells. Biochem Biophys Res Commun. 2007;353:189–194.

    Article  CAS  PubMed  Google Scholar 

  25. Suzuki A., Watanabe H., Mizutani T., Sato T., Ohta Y., Iguchi T. Global gene expression in mouse vagina exposed to diethylstilbestrol at different ages. Exp Biol Med (Maywood). 2006;231:632–640.

    Article  CAS  Google Scholar 

  26. den Hollander P., Rayala SK, Coverley D., Kumar R. Ciz1, a Novel DNA-binding coactivator of the estrogen receptor alpha, confers hypersensitivity to estrogen action. Cancer Res. 2006;66:11021–11029.

    Article  CAS  Google Scholar 

  27. Thomassin H., Flavin M., Espinas ML, Grange T. Glucocorticoid-induced DNA demethylation and gene memory during development. Embo J. 2001;20:1974–1983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li S., Washburn KA, Moore R., et al. Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus. Cancer Res. 1997;57:4356–4359.

    CAS  PubMed  Google Scholar 

  29. Ho SM, Tang WY, Belmonte de Frausto J., 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;66:5624–5632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taniuchi K., Nishimori I., Takeuchi T., Fujikawa-Adachi K., Ohtsuki Y., Onishi S. Developmental expression of carbonic anhydrase-related proteins VIII, X, and XI in the human brain. Neuroscience. 2002;112:93–99.

    Article  CAS  PubMed  Google Scholar 

  31. Supuran CT, Scozzafava A. Carbonic anhydrases as targets for medicinal chemistry. Bioorg Med Chem. 2007;15:4336–4350.

    Article  CAS  PubMed  Google Scholar 

  32. Nishikata M., Nishimori I., Taniuchi K., et al. Carbonic anhydrase-related protein VIII promotes colon cancer cell growth. Mol Carcinog. 2007;46:208–214.

    Article  CAS  PubMed  Google Scholar 

  33. Tsibris JCM, Segars J., Enkemann S., et al. New and old regulators of uterine leiomyoma growth from screening with DNA arrays. Fertil Steril. 2003;80:279.

    Article  PubMed  Google Scholar 

  34. Kelly BA, Bond BC, Poston L. Gestational profile of matrix metalloproteinases in rat uterine artery. Mol Hum Reprod. 2003;9:351–358.

    Article  CAS  PubMed  Google Scholar 

  35. Lemaitre V., D’Armiento J. Matrix metalloproteinases in development and disease. Birth Defects Res C Embryo Today. 2006;78:1–10.

    Article  CAS  PubMed  Google Scholar 

  36. Croteau W., Davey JC, Galton VA, St Germain DL Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. J Clin Invest. 1996;98:405–417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wasco EC, Martinez E., Grant KS, St Germain EA, St Germain DL, Galton VA Determinants of iodothyronine deiodinase activities in rodent uterus. Endocrinology. 2003;144:4253–4261.

    Article  CAS  PubMed  Google Scholar 

  38. Wasco EC, Martinez E., Grant KS, St. Germain EA, St. Germain DL, Galton VA Determinants of iodothyronine deiodinase activities in rodent uterus. Endocrinology. 2003;144:4253–4261.

    Article  CAS  PubMed  Google Scholar 

  39. Ambroziak M., Pachucki J., Stachlewska-Nasfeter E., Nauman J., Nauman A. Disturbed expression of type 1 and type 2 iodothyronine deiodinase as well as titf1/nkx2-1 and pax-8 transcription factor genes in papillary thyroid cancer. Thyroid. 2005;15:1137–1146.

    Article  CAS  PubMed  Google Scholar 

  40. Kim BW, Daniels GH, Harrison BJ, et al. Overexpression of Type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels. J Clin Endocrinol Metab. 2003;88:594–598.

    Article  CAS  PubMed  Google Scholar 

  41. Curcio C., Baqui MM, Salvatore D., et al. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J. Biol. Chem. C100325200.

  42. Song S., Oka T. Regulation of type II deiodinase expression by EGF and glucocorticoid in HC11 mouse mammary epithelium. Am J Physiol Endocrinol Metab. 2003;284:E1119–1124.

    Article  CAS  PubMed  Google Scholar 

  43. Cunningham NS, Jenkins NA, Gilbert DJ, Copeland NG, Reddi AH, Lee SJ Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3. Growth Factors. 1995;12:99–109.

    Article  CAS  PubMed  Google Scholar 

  44. Hino J., Kangawa K., Matsuo H., Nohno T., Nishimatsu S. Bone morphogenetic protein-3 family members and their biological functions. Front Biosci. 2004;9:1520–1529.

    Article  CAS  PubMed  Google Scholar 

  45. Katoh Y., Katoh M. Comparative integromics on BMP/GDF family. Int J Mol Med. 2006;17:951–955.

    CAS  PubMed  Google Scholar 

  46. Yu J., Zhu T., Wang Z., et al. A Novel set of DNA methylation markers in urine sediments for sensitive/specific detection of bladder cancer. Clin Cancer Res. 2007;13:7296–7304.

    Article  CAS  PubMed  Google Scholar 

  47. Kraunz KS, Nelson HH, Liu M., Wiencke JK, Kelsey KT Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer. Br J Cancer. 2005;93:949–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Dou Q., Zhao Y., Tarnuzzer RW, et al. Suppression of transforming growth factor-beta (TGF beta) and TGF beta receptor messenger ribonucleic acid and protein expression in leiomyomata in women receiving gonadotropin-releasing hormone agonist therapy. J Clin Endocrinol Metab. 1996;81:3222–3230.

    CAS  PubMed  Google Scholar 

  49. Bruns ME, Overpeck JG, Smith GC, Hirsch GN, Mills SE, Bruns DE Vitamin D-dependent calcium binding protein in rat uterus: differential effects of estrogen, tamoxifen, progesterone, and pregnancy on accumulation and cellular localization. Endocrinology. 1988;122:2371–2378.

    Article  CAS  PubMed  Google Scholar 

  50. Christakos S., Gabrielides C., Rhoten WB Vitamin D-dependent calcium binding proteins: chemistry, distribution, functional considerations, and molecular biology. Endocr Rev. 1989;10:3–26.

    Article  CAS  PubMed  Google Scholar 

  51. Hong EJ, Choi KC, Jeung EB Induction of calbindin-D9k messenger RNA and protein by maternal exposure to alkylphenols during late pregnancy in maternal and neonatal uteri of rats. Biol Reprod. 2004;71:669–675.

    Article  CAS  PubMed  Google Scholar 

  52. Lee GS, Choi KC, Kim HJ, Jeung EB Effect of genistein as a selective estrogen receptor beta agonist on the expression of calbindin-D9k in the uterus of immature rats. Toxicol Sci. 2004;82:451–457.

    Article  CAS  PubMed  Google Scholar 

  53. An BS, Kang SK, Shin JH, Jeung EB Stimulation of calbindin-D(9k) mRNA expression in the rat uterus by octylphenol, nonylphenol and bisphenol. Mol Cell Endocrinol. 2002;191:177–186.

    Article  CAS  PubMed  Google Scholar 

  54. Krisinger J., Dann JL, Currie WD, Jeung EB, Leung PC Calbindin-D9k mRNA is tightly regulated during the estrous cycle in the rat uterus. Mol Cell Endocrinol. 1992;86:119–123.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Carcinogenesis, MD Anderson Cancer Center, Science Park Research Division, 1808 Park Rd 1C, PO Box 389, Smithville, Texas, 78957, USA

    K. L. Greathouse MS, RD, K. Lin MS, T. D. Berry BS, T. G. Bredfeldt PhD & C. L. Walker PhD

  2. Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    J. D. Cook PhD

  3. Millennium Pharmaceuticals, Cambridge, Massachusetts, USA

    B. J. Davis VMD, PhD

  4. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

    B. J. Davis VMD, PhD

Authors
  1. K. L. Greathouse MS, RD
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  2. J. D. Cook PhD
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  3. K. Lin MS
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  4. B. J. Davis VMD, PhD
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  5. T. D. Berry BS
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  6. T. G. Bredfeldt PhD
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  7. C. L. Walker PhD
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Correspondence to C. L. Walker PhD.

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Greathouse, K.L., Cook, J.D., Lin, K. et al. Identification of Uterine Leiomyoma Genes Developmentally Reprogrammed by Neonatal Exposure to Diethylstilbestrol. Reprod. Sci. 15, 765–778 (2008). https://doi.org/10.1177/1933719108322440

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  • DOI: https://doi.org/10.1177/1933719108322440

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