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Reproductive Sciences, Vol. 14, No. 2, 121-136 (2007)
DOI: 10.1177/1933719106298401

Identification of a Sensitive Period for Developmental Programming That Increases Risk for Uterine Leiomyoma in Eker Rats

Jennifer DeAnn Cook, PhD

Science Park-Research Division, University of Texas M.D. Anderson Cancer Center, Smithville, Graduate School of Biomedical Sciences, University of Texas Houston Health Science Center, Houston

Barbara J. Davis, DMV, PhD

Laboratory of Women's Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina

Julia Alicia Goewey, BS

Science Park-Research Division, University of Texas M.D. Anderson Cancer Center, Smithville

Tia D. Berry, BS

Science Park-Research Division, University of Texas M.D. Anderson Cancer Center, Smithville

Cheryl Lyn Walker, PhD

Science Park-Research Division, University of Texas M.D. Anderson Cancer Center, Smithville, chwalker{at}mdanderson.org

Epidemiological and experimental animal studies have shown that exposure to xenoestrogens during reproductive tract development reprograms target tissues, leading to increased disease risk later in adult life. To understand what defines the critical risk period for this effect, termed developmental programming, the authors assess the sensitivity of the female reproductive tract to developmental programming during various stages of neonatal development. Eker rats, which are predisposed to develop uterine leiomyoma because of a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor suppressor gene, were exposed to the xenoestrogen diethylstilbestrol (DES) on either postnatal days 3 to 5, 10 to 12, or 17 to 19, 3 important periods of reproductive tract development and differentiation. Developmental programming was observed in both carrier (Tsc-2Ek/+) and wild-type (Tsc-2 +/+) rats exposed to DES at days 3 to 5 and days 10 to 12 but not in rats exposed at days 17 to 19. Developmental programming resulted in increased tumor suppressor gene penetrance in Tsc-2Ek/+ females relative to vehicle controls. In contrast, DES exposure at days 17 to 19 did not significantly increase the incidence of uterine leiomyoma in carrier females, indicating that the window of susceptibility had closed by this time. Gene expression analysis to determine what defined the susceptible (days 3-5 and days 10-12) versus resistant (days 17-19) periods revealed that in adult myometrium, expression of the estrogen-responsive genes calbindin D9K and progesterone receptor had been reprogrammed in females exposed to DES at days 3 to 5 and days 10 to 12 but not in those exposed at days 17 to 19. Reprogramming in response to DES exposure resulted in a hyperresponsiveness to ovarian hormones and could be prevented by ovariectomy prior to sexual maturity. Furthermore, in the neonatal uterus, DES was equally effective at inducing transcription of estrogen-responsive genes during both sensitive and resistant periods, indicating that resistance to developmental programming was not due to an inability of the estrogen receptor to transactivate gene expression. Interestingly, the resistant period coincided with the time at which reproductive tract tissues are exposed to endogenous estrogen, suggesting that target tissues are most vulnerable to developmental programming during the period in which they would normally be maintained in an estrogen-naïve state.

Key Words: Developmental programming • xenoestrogens • tumor suppressor gene • Eker rat • tuberous sclerosis complex 2 • uterine leiomyoma.

References

  • Smith OW, Smith Gbs, Hurwitz D. Increased excretion of pregnanediol in pregnancy from diethylstilbestrol with special reference to the prevention of late pregnancy accidents. Am J Obstet Gynecol. 1946;51:441-415.[ISI]
  • 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.[ISI][Medline] [Order article via Infotrieve]
  • Herbst AL Behavior of estrogen-associated female genital tract cancer and its relation to neoplasia following intrauterine exposure to diethylstilbestrol (DES). Gynecol Oncol. 2000;76: 147-156.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • FDA Drug Bulletin: Diethylstilbestrol Contraindicated in Pregnancy. Washington, DC: US Department of Health, Education, and Welfare; 1971.
  • Baird DD, Newbold R. Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development. Reprod Toxicol. 2005; 20(1):81-84.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Missmer SA, Hankinson SE, Spiegelman D., Barbieri RL, Michels KB, Hunter DJ In utero exposures and the incidence of endometriosis. Fertil Steril. 2004;82:1501-1508.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Newbold RR Lessons learned from perinatal exposure to diethylstilbestrol. Toxicol Appl Pharmacol. 2004;199:142-150.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Newbold RR, Bullock BC, McLachlan JA Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis. Cancer Res. 1990;50:7677-7681.[Abstract/Free Full Text]
  • 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.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Newbold RR, Jefferson WN, Padilla-Burgos E., Bullock BC Uterine carcinoma in mice treated neonatally with tamoxifen. Carcinogenesis. 1997;18:2293-2298.[Abstract/Free Full Text]
  • Newbold RR, Banks EP, Bullock B., Jefferson WN Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer Res. 2001;61:4325-4328.[Abstract/Free Full Text]
  • Yoshida M., Katsuda S., Tanimoto T., et al. Induction of different types of uterine adenocarcinomas in Donryu rats due to neonatal exposure to high-dose p-t-octylphenol for different periods . Carcinogenesis. 2002;23:1745-1750.[Abstract/Free Full Text]
  • Chapin RE, Harris MW, Davis BJ, et al.The effects of perinatal/ juvenile methoxychlor exposure on adult rat nervous, immune, and reproductive system function. Fundam Appl Toxicol. 1997; 40:138-157.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Ojeda SR, Urbanski HF Puberty in the rat. In: Knobil E, Neill JD, eds. The Physiology of Reproduction . 2nd ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 1994.
  • Brody JR, Cunha GR Histologic, morphometric, and immunocytochemical analysis of myometrial development in rats and mice: II. Effects of DES on development. Am J Anat. 1989;186(1):21-42.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Branham WS, Sheehan DM Ovarian and adrenal contributions to postnatal growth and differentiation of the rat uterus. Biol Reprod. 1995;53:863-872.[Abstract]
  • Davis BJ,Travlos G., McShaneT. Reproductive endocrinology and toxicological pathology over the life span of the female rodent. Toxicol Pathol. 2001;29:77-83.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Sheehan DM,Young M. Diethylstilbestrol and estradiol binding to serum albumin and pregnancy plasma of rat and human. Endocrinology. 1979; 104:1442-1446.[Abstract]
  • 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.[Abstract/Free Full Text]
  • Brody JR, Cunha GR Histologic, morphometric, and immunocytochemical analysis of myometrial development in rats and mice: I. Normal development. Am J Anat. 1989; 186(1):1-20.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS, Smithies O. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A. 1993; 90:11162-11166.[Abstract/Free Full Text]
  • 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.[Abstract/Free Full Text]
  • Thomassin H. , Flavin M., Espinas ML, Grange T. Glucocorticoid-induced DNA demethylation and gene memory during development. EMBO J. 2001; 20:1974-1983.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Fuchs-Young R., Howe S., Hale L., Miles R., Walker C. Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators. Mol Carcinog. 1996;17:151-159.[CrossRef][ISI][Medline] [Order article via Infotrieve]
  • Burroughs KD , Fuchs-Young R., Davis B., Walker CL Altered hormonal responsiveness of proliferation and apoptosis during myometrial maturation and the development of uterine leiomyomas in the rat. Biol Reprod. 2000;63:1322-1330.[Abstract/Free Full Text]

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This Article
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Right arrow Articles by DeAnn Cook, J.
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Right arrow Articles by Walker, C. L.
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