ESTROGEN IMPRINTING OF PROSTATE GLAND VIA METHYLATON

描述(由申请人提供)：在发育期间，啮齿动物短暂地暴露于高剂量的天然或合成雌激素会导致前列腺生长和分化的永久性变化。这个过程被称为发育性雌激素化或雌激素印迹，随着动物年龄的增长，前列腺病变的发生率增加，包括上皮增生、严重不典型增生(PIN)和腺癌。因此，我们推测，在发育关键期，雌激素的异常暴露可能是日后患前列腺癌的一个诱因。然而，不太清楚的是，在前列腺形态发生的关键时期，暴露于低剂量雌激素或环境相关剂量的异种雌激素的影响。虽然一些研究表明对前列腺有永久性的刺激作用，但其他研究驳斥了这一数据。然而，已证实成人暴露于雌激素可以在动物模型中推动癌症的发生，这一点很重要，因为老年男性的雌激素水平会上升。由于最近在女性中的研究结果表明，发育中的低剂量雌激素暴露会使子宫对以后的雌激素暴露敏感，因此，低水平的自然或环境雌激素可能会增加对雌激素诱导的前列腺癌的易感性。我们将在本申请的特定目标1中使用大鼠新生模型来测试这种“两次击中”的场景，在该模型中，我们将评估早期暴露于高剂量和低剂量雌二醇或双酚A，然后随着动物年龄的增长而暴露于成年雌激素的影响。雌激素在激素停用后很长一段时间内对前列腺产生永久性影响的机制尚不清楚。一种可能的机制是通过特定基因发育甲基化的变化。这样的改变可能会对前列腺进行重新编程，使其在以后的生活中对疾病诱导变得更加敏感。这将在特定目标2中解决，在那里我们将使用高度创新的技术(甲基化敏感DNA指纹或MS-AP-PCR)进行差异甲基化检测，以确定在发育过程中暴露于不同剂量的雌二醇或双酚A的大鼠前列腺癌中的高甲基化基因。建立发育过程中特定基因的高甲基化(沉默)与早期雌激素暴露导致的成人前列腺癌之间的联系可能提供必要的因果关系，以阐明男性前列腺癌高发病率的胎儿基础。

DESCRIPTION (provided by applicant): Brief exposure of rodents to high doses of natural or synthetic estrogens during the developmental period results in permanent alterations in growth and differentiation of the prostate gland. This process, referred to as developmental estrogenization or estrogen imprinting, is associated with an increased incidence of prostatic lesions as the animals age including epithelial hyperplasia, severe dysplasia (PIN) and adenocarcinoma. Thus we hypothesize that abnormal estrogenic exposures during developmental critical periods may be a predisposing factor for prostatic disease later in life. Less clear, however, is the effect of exposures to low doses of estrogens or environmentally relevant doses of xenoestrogens during the critical period of prostate morphogenesis. While some have demonstrated a permanent stimulatory effect on the prostate, other investigations have refuted this data. It is established, however, that adult exposures to estrogens can drive carcinogenesis in animal models, which is significant since estrogen levels rise in the aging male. Since recent findings in the female have shown that developmental low-dose estrogen exposure can sensitize the uterus to later estrogen exposures, it is possible that low levels of natural or environmental estrogens may increase susceptibility to estrogen-induced prostatic tumors. We will test this "two-hit" scenario in Specific Aim 1 of the present application using the rat neonatal model where we will assess the effects of early exposures to high and low doses of estradiol or Bisphenol A followed by adult estrogen exposure as the animals age. The mechanism whereby estrogens permanently influence the prostate gland long after the withdrawal of the hormone is poorly understood. A possible mechanism is through alterations in developmental methylation of specific genes. Such alterations could reprogram the prostate such that it becomes more sensitive to disease induction later in life. This will be addressed in Specific Aim 2 where we will perform differential methylation detection using a highly innovative technology (methylation-sensitive DNA fingerprinting or MS-AP-PCR) to identify genes that are hypermethylated in rat prostate glands developmentally exposed to varying doses of either estradiol or Bisphenol A. Establishing a link between hypermethylation (silencing) of specific genes during development to adult-onset prostate neoplasia as a result of early estrogenic exposures may provide a cause-and-effect relationship needed to elucidate the fetal basis for the high incidence of prostate cancer in men.