Brief exposure of rats to estrogens early in life (developmental estrogenization) leads to permanent alterations in the prostate gland and is associated with an increased incidence of hyperplasia, dysplasia and adenocarcinoma with aging. Accordingly, it has been hypothesized that early estrogen exposure during developmental critical periods may be a predisposing factor for BPH and/or prostatic carcinoma. The long-term objectives of this investigation are to elucidate the cellular and molecular mechanisms by which neonatal estrogen initially imprint or transform the prostate gland. Preliminary data indicate that early estrogen exposure interrupts the process of branching morphogenesis and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. The target for estrogen's effects appear to be the periductal smooth muscle cells indicating that estrogen's effects are mediated through paracrine factors. This proposal focuses on further characterizing the transcription factors involved in differentiation, namely androgen receptor and retinoic acid receptors, and defining the paracrine signaling mechanisms which mediate estrogen's effects.
The Specific Aims are 1) Determine the molecular mechanism(s) which cause reduction of AR protein expression in prostatic cells following neonatal exposure to estrogen using half-life studies, polysome distribution analysis and RNA electrophoretic mobility shift assays, 2) Determine the role of TGFbeta1 and KGF in mediating the effects of neonatal estrogen on prostatic morphogenesis and epithelial differentiation using immunocytochemistry, Western and Northern analysis, RT-PCR, nuclear run- on assays and in vitro culture techniques, 3) Determine the effect of neonatal estrogenization on components of the extracellular matrix (ECM) or cell receptors for ECM components in prostatic tissue using immunocytochemistry, in-situ hybridization, RT-PCR, biochemical assays, differential display and organ culture, and 4) Determine the effect of neonatal estrogen exposure on the levels of retinoic acid and receptors in the developing prostate using RT-PCR, immunocytochemistry, in-situ hybridization, biochemical assays and organ culture techniques. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanism of estrogen's actions on the prostate during early development and lead to a better understanding of the hormonal and developmental basis for abnormal prostatic growth with aging, particularly in the formation of prostatic adenocarcinoma.
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