Development Estrogenization of the Rat Prostate Gland

大鼠在生命早期短暂地暴露于高剂量雌激素(发育性雌激素化)会导致前列腺的永久性变化，并与随着年龄增长而出现的增生、不典型增生和腺癌有关。因此，推测发育关键期的早期雌激素暴露可能是BPH和/或前列腺癌的易感因素。这项研究的长期目标是阐明新生儿雌激素最初影响或改变细胞和分子机制。 前列腺癌。新生儿雌激素暴露会中断分支形态发生，改变间质细胞学，并阻止某些前列腺上皮细胞进入正常分化途径。这些效应是叶特有的，为人类前列腺不同区域的不同疾病提供了一个有用的模型。我们已经确定，雌激素暴露会极大地改变前列腺类固醇受体的表达，从而有效地将前列腺发育从雄激素主导的过程转变为由雌激素、孕激素和维甲酸调节的过程。我们认为，这种调节变化的最终结果是，正常情况下决定前列腺发育的下游组织信号在离散的时间窗口期间被永久且不可挽回地改变。我们目前有 由于雌激素的作用，几个形态调节基因的叶特异性表达发生了变化，这部分解释了这一现象。为了进一步了解这一过程，本提案将侧重于Wnt基因和维甲酸作为啮齿动物前列腺癌发育雌激素的介体所起的作用。具体目标1：确定规范的和非规范的Wnt形态因子在前列腺发育中的作用。具体目标2： 确定新生儿前列腺的雌激素化是否是通过Wnt信号的改变来调节的。具体目标3：确定维甲酸在雌激素诱导的不同前列腺叶发育基因改变中的作用。包括转基因小鼠在内的几个体外和体内模型将被用来确定前列腺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要的和 足以满足雌激素表型。维甲酸通过其同源受体在直接介导雌激素暴露引起的前列腺发育变化中的作用将通过器官培养研究和几个体内模型进行评估。这些研究与前列腺的正常和病理发育有关。这些结果将进一步确定雌激素在前列腺癌早期发育中的作用机制，并有助于更好地理解随着年龄增长而异常前列腺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.