Development Estrogenization of the Rat Prostate Gland

大鼠在生命早期短暂暴露于高剂量雌激素（发育性雌激素化）导致前列腺永久性改变，并与增生、发育异常和腺癌伴衰老有关。因此，假设在发育关键期早期暴露于雌激素可能是BPH和/或前列腺癌的诱发因素。这项研究的长期目标是阐明新生儿雌激素最初印记或转化细胞的细胞和分子机制。 前列腺新生儿雌激素暴露中断分支形态发生，改变基质细胞学，并阻止某些前列腺上皮细胞进入正常分化途径。这些效应是叶特异性的，其作为人类前列腺不同区域中异质性疾病的有用模型。我们已经确定，雌激素暴露大大改变前列腺类固醇受体的表达，有效地开关前列腺的发展从雄激素为主的过程，一个调节雌激素，孕酮和类维生素A。我们建议，这种监管转变的净结果是，下游组织信号，通常决定前列腺发育过程中的离散时间窗口是永久性的和不可挽回的改变。我们目前 在几个形态调节基因中鉴定出叶特异性表达改变，作为雌激素化的结果，其部分阐明了这一现象。为了进一步了解这一过程，本建议将集中在Wnt基因和视黄酸作为啮齿动物前列腺发育雌激素化的介质的作用。具体目标1：确定典型和非典型Wnt形态发生蛋白在前列腺发育过程中的作用。具体目标二： 确定新生儿前列腺雌激素化是否通过Wnt信号的改变介导。具体目标3：确定类维生素A在介导雌激素诱导的前列腺叶发育基因改变中的作用。将采用包括转基因小鼠在内的几种体外和体内模型来鉴定前列腺Wnt基因在前列腺发育过程中的特定作用，并确定它们是否是必需的， 足够用于雌激素化表型。将通过器官培养研究和几种体内模型评估视黄酸通过其同源受体直接介导雌激素暴露引起的前列腺发育变化的作用。这些研究与前列腺的正常和病理发育有关。结果将进一步确定雌激素在早期发育过程中对前列腺的作用机制，并导致更好地了解随着年龄增长前列腺异常生长的激素和发育基础。

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.