Our goal is to determine the molecular targets of estrogenic chemicals and to establish the mechanisms by which interactions of estrogens with the developing genital tract result in permanently altered growth, differentiation, and neoplasia. Evidence suggests that steroid hormone actions in target tissues are mediated by the induction of peptide growth factors. As a first step in our studies of the reproductive tract, we and others are determining the time-dependent and cell-type expression of peptide growth factors that are associated with normal estrogen-induced proliferation (EGF, TGFalpha, IGF1, TGFbetas, PDGFs). Dysregulation of these growth factors are found following neonatal estrogen treatment which may be instrumental in the establishment of the various reproductive tract lesions. Tumor studies using female mice containing a human TGFalpha gene has revealed that inappropriate express of a growth factor increases the susceptibility of the reproductive tract to carcinogenesis. Cell culture studies have demonstrated that estrogen-like phenotype similar to that found in vivo can be induced in uterine cells simply by culturing and suggest that the extracellular environment plays a central role in the induction of tissue-specific gene expression. Because of the established role of Vitamin A in reproduction and in the maintenance of epithelial tissues, we are also investigating whether part of the biological effects of steroid hormones is through the modulation of the retinoid acid receptor pathway. To thoroughly understand the molecular mechanisms that control reproductive function, one must integrate the contribution of numerous factors such as the extracellular environment, inflammatory cells, steroid hormones, the retinoids, peptide growth factors and other endocrine hormones.
