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Neonatal Estrogen Exposure Alters the Transforming Growth Factor-ß Signaling System in the Developing Rat Prostate and Blocks the Transient p21^cip1/waf1 Expression Associated with Epithelial Differentiation¹

Departments of Urology (W.Y.C., L.B., C.W., G.S.P.) and Physiology and Biophysics (G.S.P.), University of Illinois College of Medicine, Chicago, Illinois 60612; and New York University Medical School (L.I.G.), New York, New York 10016

Address all correspondence and requests for reprints to: Gail S. Prins, Ph.D., Department of Urology, M/C 955, 820 South Wood Street, Chicago, Illinois 60612. E-mail: gprins{at}uic.edu

Exposure of male rats to estrogens during the neonatal period retards prostate branching morphogenesis, blocks epithelial differentiation, and predisposes the adult prostate to hyperplasia and dysplasia. The mechanism of neonatal estrogenization is not well understood. The present study evaluated transforming growth factor-ß (TGFß) in the neonatally estrogenized ventral prostate to determine whether this paracrine/autocrine factor may in part mediate the effects of estrogen on the developing prostate gland. Immunocytochemistry using antibodies against active TGFß1 and its latency-associated peptide localized this molecule to the periductal smooth muscle cells in the developing prostate. Although neonatal estrogenization increased the accumulation of total and active TGFß1 in the smooth muscle layer as early as day 6 of life, it was physically separated from the epithelial ducts by a proliferating layer of fibroblasts surrounding the basement membrane. RT-PCR demonstrated that alterations in TGFß1 levels were not due to alterations in TGFß1 transcription. TGFß2 and TGFß3 were primarily immunolocalized to differentiating epithelial cells in developing prostates, and this was markedly dampened between days 10–30 after neonatal estrogen exposure. Immunocytochemistry for TGFß signaling components revealed that neonatal estrogenization transiently reduced TGFß type I receptor levels in the prostate epithelium, but not in stroma, between days 6–15, whereas there was no effect on TGFß type II receptor. Levels of the intracellular signal Smad2 (52 kDa) were detected in epithelial cells but were not altered after estrogenization. To analyze the functional status of the TGFß signaling pathway, immunocytochemistry was performed for p21^cip-1/waf-1, a cyclin-dependent kinase inhibitor that is inducible by TGFß1 in the prostate. Transient nuclear localization of p21^cip-1/waf-1 was normally observed in epithelial cells between days 6–15 and was associated with entry of cells into a terminal differentiation pathway. Neonatal estrogenization prevented this transient expression of p21^cip-1/waf-1. The present findings demonstrate that the TGFß signaling system is perturbed at several levels in the estrogenized prostate, which may in part account for the epithelial cell differentiation blockade as well as the proliferation of periductal fibroblasts in this model.

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