THE DEVELOPMENTAL PATTERN OF ANDROGEN RECEPTOR EXPRESSION IN RAT PROSTATE LOBES IS ALTERED AFTER NEONATAL EXPOSURE TO ESTROGEN

Brief administration of estrogen to newborn rats permanently imprints adult prostatic androgen receptor (AR) expression in a lobe-specific manner. To delineate this effect, we examined the immediate effects of early estrogen exposure on the changing AR pattern in the developing ventral, dorsal, and lateral prostate lobes. Antibodies against rat AR (PG-21) were used in combination with several antibodies to cell-specific antigens for positive cellular identification by immunocytochemistry. At birth, mesenchymal cells of the ventral prostate were strongly AR positive (AR+). Epithelial cells stained only for basal cell cytokeratins and, in contrast to earlier reports, many were AR+ on day 1. Between days 3-5, periductal mesenchymal cells differentiated into smooth muscle cells which retained strong AR+ staining, whereas interductal fibroblasts exhibited a decreased incidence of ARC cells. Between days 5-10, luminal epithelial cells first appeared, and a striking increase in AR staining intensity was noted relative to that in the basal cells. During puberty, basal cells lost their AR immunoreactivity. Similar changes were observed in the dorsal and lateral lobes. Newborn rats were given 25 mu g estradiol benzoate on days 1, 3, and 5 and were killed thereafter. By day 6, AR staining was markedly decreased to a weak to moderate intensity in all cell types, and by day 10, AR was virtually absent in the separate lobes. Growth and epithelial cytodifferentiation were significantly retarded. Between days 15-30, evidence of luminal cell cytodifferentiation was noted; however, this was frequently not associated with an increase in AR staining. In the ventral and dorsal lobes, a continuous peripheral layer of AR-negative basal cells surrounded the ducts in the central and proximal regions, and this was associated with a permanent inability of luminal epithelial cells to express AR. Epithelial and smooth muscle AR expression was observed only in the distal tips. In contrast, AR expression rapidly returned in all regions of the lateral lobes, except the proximal ducts. We conclude that 1) basal epithelial cells express AR as early as day 1 of life and should be considered as possible direct targets of androgen action during prostate morphogenesis; 2) differentiation into luminal cells is associated with an increase, rather than an induction, of AR expression; and 3) periductal smooth muscle cells retain strong AR expression throughout development and should be considered primary targets for androgen-mediated morphogenesis. Neonatal estrogen initially down-regulates AR expression in all cells of the three lobes, which may explain the overall growth retardation. Although recovery is observed in the lateral lobe, proximal and central regions of the ventral and dorsal lobes remain permanently undifferentiated and unable to express AR, thus explaining the regional heterogeneity observed in adulthood.