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.
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