Studies have continued to determine the molecular and cellular targets of estrogenic chemicals and establish the mechanisms by which interactions of estrogens with developing genital tract target cells result in permanently altered differentiation, including dysmorphology and neoplasia. In the period covered by the report, the developmentally estrogenized mouse model has continued to be used to understand both the development of the mammalian genital tract as well as the mechanisms underlying hormonally associated cancers. Ninety percent of mice treated neonatally with diethylstilbestrol (DES) later express uterine adenocarinoma, which is hormonally dependent and requires a second exposure to estrogen at puberty for expression. It was determined that the immature mouse uterus, which is an especially sensitive tissue for estrogen-induced cancers, had abundant estrogen receptors (ER) in the underlying stroma, while the epithelium was relatively deficient in detectable ER. This raises the possibility that ER deficient cells may be those which are most susceptible to neoplastic transformation, leading us to explore complementary mechanisms for cell proliferation, including estrogen associated growth factors. We demonstrated, in this reporting period, that estrogen induced proliferation of the mouse uterine epithelium in vitro could be blocked by addition of antibodies to epidermal growth factor (EGF) suggesting a role for growth factor mediation of estrogen action. We also recently demonstrated the expression of the mRNA for a uterine secretory protein in the seminal vesicle of developmentally estrogenized male mice, the first example of pseudohermaphroditism at the molecular level. Studies on the metabolism of estrogens to reactive forms have shown that the mouse uterus forms catechol estrogens and that the enzyme responsible for their inactivation is relatively low. This provides a mechanism for generation of reactive estrogenic metabolites close to the target cell.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES070060-15
Application #
3941580
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
1987
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Adewale, Heather B; Jefferson, Wendy N; Newbold, Retha R et al. (2009) Neonatal bisphenol-a exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons. Biol Reprod 81:690-9
Newbold, Retha R; Jefferson, Wendy N; Padilla-Banks, Elizabeth (2009) Prenatal exposure to bisphenol a at environmentally relevant doses adversely affects the murine female reproductive tract later in life. Environ Health Perspect 117:879-85
Delclos, K Barry; Weis, Constance C; Bucci, Thomas J et al. (2009) Overlapping but distinct effects of genistein and ethinyl estradiol (EE(2)) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies. Reprod Toxicol 27:117-32
Ruhlen, Rachel L; Howdeshell, Kembra L; Mao, Jiude et al. (2008) Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the ""fetal estrogenization syndrome"" and obesity in CD-1 mice. Environ Health Perspect 116:322-8
Tang, Wan-Yee; Newbold, Retha; Mardilovich, Katerina et al. (2008) Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology 149:5922-31
Newbold, Retha R; Padilla-Banks, Elizabeth; Jefferson, Wendy N et al. (2008) Effects of endocrine disruptors on obesity. Int J Androl 31:201-8
Newbold, Retha R (2008) Prenatal exposure to diethylstilbestrol (DES). Fertil Steril 89:e55-6
Chen, Ying; Jefferson, Wendy N; Newbold, Retha R et al. (2007) Estradiol, progesterone, and genistein inhibit oocyte nest breakdown and primordial follicle assembly in the neonatal mouse ovary in vitro and in vivo. Endocrinology 148:3580-90
Jefferson, Wendy N; Padilla-Banks, Elizabeth; Newbold, Retha R (2007) Disruption of the developing female reproductive system by phytoestrogens: genistein as an example. Mol Nutr Food Res 51:832-44
Jefferson, Wendy N; Padilla-Banks, Elizabeth; Newbold, Retha R (2007) Disruption of the female reproductive system by the phytoestrogen genistein. Reprod Toxicol 23:308-16

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