To better understand direct and indirect androgen action on rat prostatic growth and function, the various cell populations within the intact adult ventral, dorsal, and lateral prostate lobes were characterized for the presence or absence of androgen receptor (AR). Polyclonal rabbit antibodies raised against amino acids 1-21 of the rat AR (PG-21) were used in combination with a library of monoclonal antibodies directed against cell-specific antigens for positive cellular identification. Luminal epithelial cells were strongly AR positive, with an order of ventral greater than lateral greater than or equal to dorsal. In the lateral lobe, staining intensity was strongest in the peripheral regions, whereas a similar gradient was not apparent in the ventral and dorsal prostate. Basal epithelial cells were AR negative in all regions of the three lobes. Periacinar smooth muscle was strongly positive for AR, and this staining did not vary with the thickness of the muscle layer. Endothelial cells of the vasculature were AR negative, while the perivascular smooth muscle cells were AR positive. The majority of stromal fibroblasts were AR negative, although a number of AR-positive fibroblastic-appearing cells were observed within the ventral and dorsal lobes. Staining with ED2, a specific marker for tissue macrophages, revealed that fixed macrophages were present in significant quantities in the stroma of intact rat prostate lobes. Since these were frequently identified as AR positive, macrophages may partially account for the appearance of AR-positive stromal cells. Thus, the present findings indicate a complex pattern of AR expression among different cell types of the three prostate lobes. Cells types that express AR can potentially be considered as direct targets of androgen action, whereas those lacking AR should be considered as indirect targets or androgen-insensitive cells.
Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period -from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures -results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.
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 AR+ 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 micrograms 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 three lobes, which may explain the overall growth retardation.(ABSTRACT TRUNCATED AT 400 WORDS)
Brief exposure of rats to high-dose estrogen during the neonatal period interrupts prostate development in a lobe-specific manner and predisposes the gland to dysplasia with aging, a phenomenon referred to as developmental estrogenization. Our previous studies have revealed that these effects are initiated through altered steroid receptor expression; however, the immediate downstream targets remain unclear. We have recently shown that developmental expression of Shh-ptc-gli is downregulated in the dorsolateral prostate following estrogenization, and this is responsible, in part, for branching deficits observed in that prostatic region specifically. In the present study, we examine the role of Fgf10 signaling during rat prostate development and as a mediator of the developmental estrogenized phenotype. Fgf10 and FgfR2iiib localize to the distal signaling center of elongating and branching ducts in separate prostate lobes where they regulate the expression of multiple morphoregulatory genes including Shh, ptc, Bmp7, Bmp4, Hoxb13, and Nkx3.1. Ventral and lateral lobe organ cultures and mesenchyme-free ductal cultures demonstrate a direct role for Fgf10/FgfR2iiib in ductal elongation, branching, epithelial proliferation, and differentiation. Based on these findings, a model is proposed depicting the localized expression and feedback loops between several morphoregulatory factors in the developing prostate that contribute to tightly regulated branching morphogenesis. Similar to Shh-ptc-gli, neonatal estrogen exposure downregulates Fgf10, FgfR2iiib, and Bmp7 expression in the dorsolateral prostate while ventral lobe expression of these genes is unaffected. Lateral prostate organ culture experiments demonstrate that growth and branching inhibition as well as Fgf10/FgfR2iiib suppression are mediated directly at the prostatic level. Furthermore, exogenous Fgf10 fully rescues the growth and branching deficits due to estrogen exposure. Together, these studies demonstrate that alterations in Fgf10 signaling are a proximate cause of Shh-ptc-gli and Bmp7 downregulation that together result in branching inhibition of the dorsolateral prostate following neonatal estrogen exposure.
Evidence supporting an early origin of prostate cancer is growing. We demonstrated previously that brief exposure of neonatal rats to estradiol or bisphenol A elevated their risk of developing precancerous lesions in the prostate upon androgen-supported treatment with estradiol as adults. Epigenetic reprogramming may be a mechanism underlying this inductive event in early life, because we observed overexpression of phosphodiesterase 4D variant 4 (Pde4d4) through induction of hypomethylation of its promoter. This epigenetic mark was invisible in early life (postnatal d 10), becoming apparent only after sexual maturation. Here, we asked whether other estrogen-reprogrammable epigenetic marks have similar or different patterns in gene methylation changes throughout life. We found that hypomethylation of the promoter of nucleosome binding protein-1 (Nsbp1), unlike Pde4d4, is an early and permanent epigenetic mark of neonatal exposure to estradiol/bisphenol A that persists throughout life, unaffected by events during adulthood. In contrast, hippocalcin-like 1 (Hpcal1) is a highly plastic epigenetic mark whose hypermethylation depends on both type of early-life exposure and adult-life events. Four of the eight genes involved in DNA methylation/demethylation showed early and persistent overexpression that was not a function of DNA methylation at their promoters, including genes encoding de novo DNA methyltransferases (Dnmt3a/b) and methyl-CpG binding domain proteins (Mbd2/4) that have demethylating activities. Their lifelong aberrant expression implicates them in early-life reprogramming and prostate carcinogenesis during adulthood. We speculate that the distinctly different fate of early-life epigenetic marks during adulthood reflects the complex nature of lifelong editing of early-life epigenetic reprogramming.
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