Continuing studies are designed to determine the cellular and molecular mechanisms underlying the interactions of naturally occurring and synthetic estrogenic compounds with various target tissues (the developing genital tract, gonads, liver, mammary tissues, and bone tissue) which result in permanent alterations in differentiation including dysmorphology and neoplasia. Diethylstilbestrol (DES) is used as a model estrogenic compound. In vivo studies in which DES exposure occurs during development (prenatal and/or neonatal) of the genital tract have shown various benign and malignant lesions in female and male mice which are similar to those reported in humans exposed to DES. The immunocytochemical and molecular genetic characteristics of the DES-induced murine tumors are being studied and compared to those seen in human malignancies. Descendants of the tumor-bearing mice are being followed for reproductive assessment and potential increased susceptibility to tumors. The ontogeny of lactoferin (LF), complement C3, decay-accelerating factor (DAF), and the estrogen receptor (ER) in the developing reproductive tract are being mapped in vivo and in vitro to determine early estrogenic responses and the role of ER in these responses. In addition, transgenic mice which are overexpressing the estrogen receptor have been treated developmentally with DES to determine if the ER is playing a role in the induction and/or progression of uterine neoplasia. Dysmorphology in the genital tract of mice exposed developmentally to DES includes the persistent gene expression of uterine LF and various growth factors including TGF-alpha and EGF which may be preneoplastic markers. Since many fundamental questions remain concerning the roles of growth factors, growth inhibitors, and receptors, studies continue to identify additional human and mouse genes, that characterize the different physiological states of normal and neoplastic tissue. Studies determining cell proliferation rates and apoptotic rates in target tissues exposed developmentally to DES have given further insights into mechanisms of DES-toxic effects. Effects of Tamoxifen on developing estrogen target tissues are being studied and dysmorphology and neoplastic potential compared to DES. Compounds reported to be carcinogenic in NTP rodent bioassays are being tested for estrogenic potency. Together, these studies suggest a complex pattern of differentiation and development in hormone responsive target-tissues and provide important clues for mechanisms involved in the development of neoplasia.
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