Brief exposure of rats to estrogen 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 estrogens initially imprint or transform the prostate gland. In the past grant periods, we have collected significant evidence to show that early estrogen exposure interrupts the process of branching morphogenesis, alters stromal cytology associated with the budding prostatic ducts and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. These alterations are mediated, in part, through transient and permanent perturbations in steroid receptor expression in the prostate. Evidence also documents that TGFbeta paracrine communication between stromal and epithelial cells is interrupted following neonatal estrogenization. Preliminary evidence now leads us to hypothesize that several key developmental pathways downstream of steroid receptor action are permanently altered following estrogenic exposure. This proposal focuses on further characterizing specific developmental genes involved in prostate morphogenesis that are regulated by estrogens.
The specific aims of the new proposal are:
Specific Aim 1 : Determine the regulatory role of fetal and neonatal estrogen on the expression of prostate homeobox genes (Hox 13 and Nkx3.1) during prostatic morphogenesis and epithelial differentiation.
Specific Aim 2 : Determine the effects of developmental estrogenization on secreted regulatory genes (Shh, Wnts, BMPs, Fgf) and their cognate receptors which mediate epithelial-mesenchymal communication during prostate development. Both in vivo and in vitro models will be employed to investigate the temporal and spatial expression of these developmental genes and their hormonal regulation. Methods include immunocytochemistry, in situ hybridization, laser capture microscopy followed by RT-PCR, Northern and Western analysis, receptor antagonists and micronized ligand or antibody applications. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanism of action 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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