ESTROGEN IMPRINTING OF PROSTATE GLAND VIA METHYLATON

描述（由申请方提供）：啮齿动物在发育期间短暂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改变。这一过程被称为发育雌激素化或雌激素印记，与前列腺病变的发生率随着动物年龄的增长而增加有关，包括上皮增生、重度异型增生（PIN）和腺癌。因此，我们推测，在发育关键期异常雌激素暴露可能是前列腺疾病的诱发因素在以后的生活。 然而，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尚不清楚。虽然一些研究已经证明了对前列腺的永久刺激作用，但其他研究反驳了这一数据。然而，已经确定的是，成年人暴露于雌激素可以在动物模型中驱动致癌作用，这是重要的，因为雌激素水平在老年男性中升高。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可以使子宫对以后的雌激素暴露敏感，因此低水平的天然或环境雌激素可能会增加对雌激素诱导的前列腺肿瘤的易感性。我们将使用大鼠新生儿模型在本申请的具体目标1中测试这种“两次打击”情况，其中我们将评估早期暴露于高剂量和低剂量的雌二醇或双酚A，然后随着动物年龄增长暴露于成年雌激素的影响。雌激素在停用激素很长时间后仍能永久影响前列腺的机制还知之甚少。一个可能的机制是通过改变特定基因的发育甲基化。这种改变可以重新编程前列腺，使其在以后的生活中对疾病诱发变得更加敏感。这将在具体目标2中解决，我们将使用高度创新的技术（甲基化敏感的DNA指纹或MS-AP-PCR）进行差异甲基化检测，以鉴定发育暴露于不同剂量雌二醇或双酚A的大鼠前列腺中高甲基化的基因。在发育过程中特定基因的高甲基化（沉默）与成人发病的前列腺肿瘤之间建立联系，作为早期雌激素暴露的结果，可能提供一种因果关系，需要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.