Brief exposure of rats to high doses of estrogens early in life (developmental estrogenization) leads to permanent alterations in the prostate gland and is associated with hyperplasia, dysplasia and adenocarcinoma with aging. Accordingly, it is 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. Neonatal estrogen exposure interrupts branching morphogenesis, alters stromal cytology and blocks certain prostatic epithelial cells from entering a normal differentiation pathway. These effects are lobe-specific which serves as a useful model for heterogeneous diseases in different zones of the human prostate gland. We have determined that estrogen exposure drastically alters prostatic steroid receptor expression which effectively switches prostate development from an androgen-dominated process to one regulated by estrogens, progesterone, and retinoids. We propose that the net result of this regulatory shift is that downstream organizational signals which normally dictate prostate development during discrete temporal windows are permanently and irretrievably altered. We have presently identified lobe-specific expression alterations in several morphoregulatory genes as a result of estrogenization which partially elucidates this phenomenon. To further understand this process, the present proposal will focus on the roles of Wnt genes and retinoic acids as mediators of developmental estrogenization of the rodent prostate gland.
Specific Aim 1 : Determine the roles for canonical and noncanonical Wnt morphogens during prostate development.
Specific Aim 2 : Determine whether neonatal estrogenization of the prostate is mediated through alterations in Wnt signaling.
Specific Aim 3 : Determine the role of retinoids in mediating the estrogen-induced alterations of developmental genes in the separate prostate lobes. Several in vitro and in vivo models including transgenic mice will be employed to identify specific roles for prostatic Wnt genes during prostate development and to determine whether they are necessary and sufficient for the estrogenized phenotype. The roles of retinoic acids via their cognate receptors in directly mediating changes in prostate development initiated by estrogen exposure will be assessed with organ culture studies and several in vivo models. These studies are related to the normal and pathologic development of the prostate gland. Results will further define the mechanisms of estrogen's actions on the prostate gland during early development and lead to a better understanding of the hormonal and developmental basis for abnormal prostate growth with aging.
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