Developmental Reprogramming of Prostate Carcinogenesis by BPA

描述（由申请人提供）：发育重编程是早期暴露于环境因素增加对成人疾病易感性的重要机制。对于双酚a等异种雌激素，需要进一步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编程。异种雌激素可以在不同的组织中作为激动剂或拮抗剂，这也表明需要更好地了解特异性内质网协同调节剂（CoR）如何影响其活性。最后，需要进一步的研究来确定重编程的表观遗传效应，这种效应会持续到成年期，并成为包括前列腺癌（PCa）在内的成人疾病的基础。这项“大机遇”（GO）资助通过对双酚a如何诱导发育重编程以增加前列腺癌易感性的综合机制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，以确定与发育重编程和PCa风险增加相关的变化；2)确定特定ER亚型和CoRs作为BPA活性决定因素的作用。这个项目适合获得政府资助：它规模大；多研究者、多机构、多学科；将解决一个特定的研究需求，并在2年内产生重大的研究影响。该研究团队为实现目标做好了独特的准备，该项目现在已经准备好实施，利用创新技术，其结果将推进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BPA的新生儿将被跟踪到成年期，以量化BPA相关的前列腺病变，以及病变的易感性将与BPA诱导的前列腺表观基因组变化相关。这些研究将通过相关疾病终点（PIN和癌）的口服暴露、内部剂量测量和剂量反应数据来填补双酚a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异性er (？，还是？Homo -和？/？异二聚体)、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。

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.