This collaborative effort deals with the development of the human female and male reproductive tracts. Human fetal male genital tracts will be grafted to athymic nude mice and the effects of diethylstilbestrol (DES) will be examined. The effects of DES on the developing human male genital tract will be examined morphologically by light and electron microscopy, by steroid autoradiography to assess androgen and estrogen receptors, and by morphometrics to assess the development of mesenchymal organization. Morphogenesis of human female genital tracts will be examined in terms of the development of mesenchymal differentiation into fibroblastic and smooth muscle cells and structural (circumferential) organization by morphometry, the expression of estrogen receptors by autoradiography and immunocytochemistry, and ultrastructural features. Utilizing rats and mice, we will examine the role of cell-cell interactions during the process of regression of the Mullerian ducts (MD) and will determine whether MD epithelium and mesenchyme can respond directly to Mullerian inhibiting substance (MIS). The mesenchymal specificity of MD regression will be explored, and the age-dependent loss of sensitivity of the MD to MIS will be examined in terms of maturational changes in epithelium versus mesenchyme. Another major effort will be directed towards examining uterine mesenchymal differentiation in the mouse and how DES perturbs this process. For this study the time course of segregation of uterine mesenchyme into fibroblastic and smooth muscle cells will be determined. The emergence of structural (circumferential) orientation will be explored in uteri of normal and DES-treated mice, which exhibit altered structural organization and differentiation of the uterus. The role of epithelial-mesenchymal interactions will also be examined during uterine mesenchymal differentiation. Another project will deal with DES-induced vaginal adenosis. Since adenosis frequently progresses to more severe pathological conditions (neoplasia), we will examine adenosis to determine its biological relatedness to uterine, cervical, or vaginal epithelium. Finally, a model for investigating instructive inductions between epithelium and mesenchyme will be pursued in the developing uterus and vagina to determine whether these interactions proceed via cell-cell contact, cell-extracellular matrix interactions, or via diffusible signals. If successful, we will embark on a study to isolate the inductor molecules.
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