Exposure to estrogens during critical periods of the development induces teratogenic and carcinogenic lesions of the reproductive tracts of humans and animals. Our goal is to determine the molecular and cellular 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. Our research has sought to elucidate the role of peptide growth factors in reproductive function and steroid hormone action. We have found that estrogen regulates the RNA levels of several multifunctional peptides such as EGF, TGF-alpha, IGFI, TGF-betas, and lactoferrin in the reproductive tract. In vivo pellet studies have shown that some of these factors can act as direct regulators of growth. Our studies have also demonstrated that exposure to estrogens during the neonatal period (a stage of development that is sensitive to estrogen-induced carcinogenesis) results in permanent alterations in the expression of some of these peptides. Early estrogen exposure produces long-term, hormone-independent induction of mRNA for lactoferrin, EGF, and actin in the vagina and cervix. The permanent induction of these genes by neonatal estrogen treatment suggests that they play an important role in reproductive tract physiology and that dysregulation may be instrumental in the establishment of the """"""""estrogenized"""""""" morphology of the vagina and in the etiology of the neoplastic lesions. Future plans are to continue to define the role of peptide mediators of estrogen action; determine the cell type responsible for the synthesis of these factors; locate the cellular target where these factors act; elucidate whether these factors act alone, synergistically or temporally; investigate the second messenger systems involved; and determine whether dysregulation of these factors contributes to the developmental toxicity of estrogens.
