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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD021966-06
Application #
3321140
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1986-09-30
Project End
1994-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
George, F W (1997) Androgen metabolism in the prostate of the finasteride-treated, adult rat: a possible explanation for the differential action of testosterone and 5 alpha-dihydrotestosterone during development of the male urogenital tract. Endocrinology 138:871-7
Bentvelsen, F M; McPhaul, M J; Wilson, C M et al. (1996) Regulation of immunoreactive androgen receptor in the adrenal gland of the adult rat. Endocrinology 137:2659-63
Bentvelsen, F M; McPhaul, M J; Wilson, J D et al. (1994) The androgen receptor of the urogenital tract of the fetal rat is regulated by androgen. Mol Cell Endocrinol 105:21-6
George, F W (1993) Postnatal expression of high rates of 5 alpha-reductase in the female rat urogenital tract. J Dev Physiol 19:187-91
Bentvelsen, F M; George, F W (1993) The fetal rat gubernaculum contains higher levels of androgen receptor than does the postnatal gubernaculum. J Urol 150:1564-6
Renfree, M B; Wilson, J D; Short, R V et al. (1992) Steroid hormone content of the gonads of the tammar wallaby during sexual differentiation. Biol Reprod 47:644-7
Lephart, E D; Ojeda, S R (1990) Hypothalamic aromatase activity in male and female rats during juvenile peripubertal development. Neuroendocrinology 51:385-93
Tannenbaum, M G; Haigh, G R; Vaughan, M K et al. (1990) Effects of acute cold exposure at night on pineal N-acetyltransferase activity and melatonin content in white-footed mice, Peromyscus leucopus. Comp Biochem Physiol A Comp Physiol 95:363-6
Takane, K K; George, F W; Wilson, J D (1990) Androgen receptor of rat penis is down-regulated by androgen. Am J Physiol 258:E46-50
George, F W (1989) Developmental pattern of 5 alpha-reductase activity in the rat gubernaculum. Endocrinology 124:727-32

Showing the most recent 10 out of 13 publications