The goals of the proposed studies in this application are to elucidate the mechanisms that regulate differentiation and function of the fetal gonads and to understand the role that hormones secreted by the differentiated ovary or testis play in subsequent development of the male and female phenotypes. It is hoped that these studies will provide clues to disorders (such as true hermaphroditism, the XX male, pure gonadal dysgenesis, the vanishing testis, etc.) that impair gonadal differentiation as well as insights into the mechanisms of androgen-dependent wolffian duct differentiation and testicular descent and possible estrogen-mediated events in differentiation and development. Using techniques established in their laboratory, the investigators propose studies to examine the role of various potential Sertoli cell factors (e.g., mullerian inhibiting substance, inhibin, TGF-beta, somatomedin C, and growth factors) on differentiation of the enzymatic pathway for steroid hormone formation in cultured fetal rabbit gonads. They plan to extend the observation that vasoactive intestinal peptide (VIP) stimulates steroidogenesis in the rat to other species, at least the rabbit, and then determine if VIP has a role in gonadal differentiation using the fetal rabbit gonadal organ culture system. They also propose studies to examine the role of 5-alpha-reduction and aromatization of testosterone in gonadal development by determining the effect of specific inhibitors of each enzyme administered in vivo on gonadal development. Identification of the cellular localization of aromatase in the newborn rat ovary will be conducted by hybridization histochemistry. Identification of the androgen receptor in the fetal wolffian duct and in the fetal/newborn gubernaculum of the rat will be carried out by autoradiography and/or hybridization histochemistry. They further plan to histochemically characterize the mesenchymal core of the rat gubernaculum; then determine what effect altering the hormonal environment, both in vivo and in vitro, has on the mesenchymal core. In vivo administration of a 5-alpha-reductase inhibitor will be used to examine postnatal androgen-dependent development of sex accessory tissues of the rat. A transplantation model will be developed to study the possible role of estrogen in urogenital tract development.
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