Developmental Reprogramming of Prostate Carcinogenesis by BPA

描述(由申请人提供)：发育重新编程是一种重要的机制，通过这种机制，早期接触环境因素会增加成人疾病的易感性。对于异种雌激素，如双酚A，需要更多的研究来了解特定的雌激素受体(ER)亚型和基因组与非基因组信号如何介导这种发育重新编程。异种雌激素可以在不同的组织中起激动剂或拮抗剂的作用，这也表明需要更好地了解特定的内质网协同调节因子(COR)如何影响其活性。最后，还需要更多的研究来确定再编程的表观遗传学影响，这种影响会持续到成年，并成为包括前列腺癌(PCa)在内的成人疾病的基础。这项重大机遇(GO)拨款通过对双酚A如何诱导发育重新编程以增加前列腺癌易感性的综合机械评估来满足这些研究需求。具体目标是1)对BPA表观基因组进行全局分析，以确定与发育重新编程和增加的PCa风险相关的变化，以及2)确定特定ER亚型和CORs作为BPA活性决定因素的作用。这个项目适用于围棋资助：它规模庞大；多个研究人员、多机构、多学科；将满足特定的研究需求，并在两年内产生重大研究影响。研究团队为实现这些目标做好了独一无二的准备，该项目现在已经准备好实施，利用创新技术，结果将推进NIH改善健康和预防疾病的使命。在前列腺发育过程中暴露于双酚A的新生儿将被跟踪到成年后对双酚A相关的前列腺病变进行量化，而发生病变的易感性将与双酚A诱导的前列腺表基因组的变化相关。这些研究将通过口腔暴露、相关疾病终点(PIN和癌症)的剂量和剂量反应数据的内部测量来填补BPA文献中的特定数据空白。体内研究将通过体外多参数机制研究来阐明特定的内质网(？，或？同性恋--还有？/？异源二聚体)、非基因组信号和p160类CORs(SRC-1、-2、-3)决定了BPA在前列腺上皮细胞中的作用。 前列腺癌在世界范围内的患病率正在上升，目前美国每6名男性中就有1人面临患上这种疾病的风险。迫切需要了解前列腺癌的早期起源，以确定是否有必要采取额外的公共卫生措施，以防止在发育的关键窗口期间暴露于双酚A或其他外来雌激素。这种高度新颖的、科学上强有力的、多学科的方法来模拟双酚A对前列腺的发育影响，将为双酚A和其他内分泌干扰物毒理学的证据权重评估设定新的标准，并将极大地推动基因-环境相互作用、非达尔文主义疾病易感性和激素受体作用领域的研究。 公共卫生相关性：我们希望在这项提案中解决的广泛问题是，与环境相关的低剂量BPA如何通过表观遗传重新编程诱导持久的染色质状态，从而增加成年后前列腺癌的易感性。识别与前列腺癌发生相关的发育可重编程的BPA-表观基因组及其在一生中的动态变化将为识别暴露和高危人群提供机会，这是前列腺癌预防的第一步。更重要的是，本申请中提出的研究将提供关于双酚A作用机制的新的和关键的机械数据，以帮助各机构制定双酚A安全使用的监管指南。

DESCRIPTION (provided by applicant): Developmental reprogramming is an important mechanism by which early life exposures to environmental agents increase susceptibility to adult disease. For xenoestrogens such as BPA, additional research is required to understand how specific estrogen receptor (ER) subtypes and genomic vs. nongenomic signaling mediate this developmental reprogramming. Xenoestrogens can act as agonists or antagonists in different tissues, also pointing to the need for a better understanding of how specific ER coregulators (CoR) influence their activity. Finally, additional research is needed to identify the epigenetic effects of reprogramming that persist into adulthood and underlie adult disease, including prostate cancer (PCa). This Grand Opportunity (GO) grant addresses these research needs with an integrated, mechanistic assessment of how BPA induces developmental reprogramming to increase susceptibility to prostate carcinogenesis. The Specific Aims are 1) Global analysis of the BPA epigenome to define changes associated with developmental reprogramming and increased PCa risk and 2) Define the role of specific ER subtypes and CoRs as determinants of BPA activity. This project is appropriate for a GO grant: it is large; multi-investigator, multi-institutional, multi-disciplinary; will address a specific research need and make a significant research impact in 2 years. The research team is uniquely poised to accomplish the objectives, the project is ready to implement now, utilizes innovative technologies, and the results will advance the NIH mission to improve health and prevent disease. Neonates exposed to BPA during prostate development will be followed into adulthood to quantitate BPA-associated prostate lesions and susceptibility to develop lesions will be correlated with BPA induced changes in the prostate epigenome. These studies will fill specific data gaps in the BPA literature with oral exposures, internal measurements of dose and dose-response data for relevant disease endpoints (PIN and carcinoma). The in vivo studies will be informed by in vitro, multi-parametric mechanistic studies to elucidate how specific ERs (?, or ? homo- and ?/? hetero-dimers), nongenomic signaling and the p160 class CoRs (SRC-1, -2, -3) determine the effects of BPA in prostate epithelial cells. The prevalence of PCa is increasing world-wide with 1 in 6 men in the US currently at risk for developing this disease. There is a tremendous need to understand the early origins of PCa to determine if additional public health measures are necessary to prevent exposure to BPA, or other xenoestrogens, during critical windows of development. This highly novel, scientifically vigorous, multidisciplinary approach to model the developmental effects of BPA on the prostate will set new standards for weight-of-evidence assessment of the toxicology of BPA and other endocrine disruptors, and will significantly advance research in the fields of gene-environment interaction, non-Darwinian disease susceptibility and hormone receptor action. PUBLIC HEALTH RELEVANCE: The broad question we wish to address in this proposal is how environmentally relevant low doses of BPA induce a long-lasting chromatin state via epigenetic reprogramming to increase the susceptibility to prostate carcinogenesis in adult life. The identification of a developmentally reprogrammable BPA-epigenome associated with prostate carcinogenesis and its dynamic changes throughout life will open opportunities to identify exposed and at-risk populations, which is the first step toward prostate cancer prevention. More importantly, the studies proposed in this application will provide the new and critical mechanistic data on the mechanism of action of BPA to assist agencies in setting regulatory guidelines for the safe use of BPA.