Studies continue to determine the cellular and molecular mechanisms by which naturally occurring and synthetic estrogenic compounds interact with various target tissues such as the developing genital tract and skeletal system to cause permanent alterations in differentiation, including dysmorphology and neoplasia. Diethylstilbestrol (DES) is used as a model estrogenic compound. In vivo studies in which DES exposure occurred during development of the murine genital tract (prenatally and/or neonatally) have shown benign and malignant lesions in both male and female animals in structures derived from the Mullerian duct. The molecular genetic features of the tumors are being studied and compared to those reported in human malignancies. Furthermore, descendants of the tumor-bearing mice are being followed for reproductive assessment and increased susceptibility to tumors. Dysmorphology in the genital tract of mice exposed developmentally to DES includes the persistent gene expression of uterine lactoferrin, TGFalpha, and EGF which may be preneoplastic markers. Studies on phospholipid turnover have shown further insights into signal transduction mechanisms associated with estrogens. Since EGF stimulates uterine cell division in the developing and mature reproductive tract, growth factors may play a role in growth and differentiation of these tissues. Furthermore, it was shown that estrogen regulates the expression of both EGF and TGFalpha. EGF reproduced the effect of estrogen on induction of DNA synthesis, lactoferrin mRNA levels, and phosphoinositide metabolism. The estrogen-like effects of EGF in the uterus of the mature mouse and uterine-derived cells in culture were dependent on the classical estrogen receptor. Together, these studies support a complex developmental progression in hormone responsiveness in the female and male genital tract with important clues for the development of neoplasia.
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