Chronic exposure to Biphenol A and uterine cancer risk markers

描述（由申请人提供）：子宫内膜癌（ECa）是女性最常见的癌症。遗传只占ECa风险的5-10%，其余的则是激素和环境的影响。观察性研究强烈支持无对抗性雌激素暴露，包括内分泌活性物质及其相关的代谢并发症与人类ECa的高风险有关。在大鼠研究中，新生儿暴露于双酚a会影响成年子宫对激素的反应，并诱发子宫萎缩、子宫增生和癌症。然而，关于更与人类相关的低剂量终身口服暴露方案的数据是不存在的。此外，潜在发病机制的分子机制仍不完全清楚。本项目旨在通过一个控制良好的GLP平台，评估慢性低剂量双酚A （BPA）暴露对子宫增生和致癌的影响，以解决这些数据缺口。目标是确定双酚a驱动的早期癌症风险标志物，以促进转化为公共卫生政策。具体目标如下。在目的1中，研究人员将建立慢性双酚a暴露与子宫不典型增生或腺癌发展之间的剂量-反应曲线，并确定在75%的2岁大鼠中诱导子宫肿瘤和/或增生/不典型增生的双酚a有效剂量。在目标2中，研究人员将使用探索方法识别bpa相关的早期ECa生物标志物，该方法结合了全基因组甲基化启动子阵列分析和全局转录组分析，以及基于知识的方法，选择一组甲基化状态在另一项正在进行的研究中被发现和证实的基因。在目标3中，研究人员将试图确定目标2中确认的候选基因变化的时间进程，以确定bpa驱动的早期子宫癌标记基因。

DESCRIPTION (provided by applicant): Endometrial cancer (ECa) is the most common cancer diagnosed in women. Genetics can only account for 5-10% of ECa risk and the rest lies in hormonally and environmentally influences. Observational studies strongly support unopposed estrogen exposure including endocrine-active substance and its associated metabolic complications are linked to a higher risk of ECa in human. In rat studies, neonatal exposure to BPA affects the adult uterine response to hormone and induced uterotrophy, uterine hyperplasia and cancer. However, data on a more human relevant exposure regimen that involves a low-dose lifespan oral exposure is non-existent. Additionally, the molecular mechanisms underlying pathogenesis remains incompletely understood. This project aims to address these data gap gaps by assessing the impact of chronic low dose exposue to bisphenol A (BPA) on uterine hyperplasia and carcinogenesis by using a well controlled GLP platform. The goal is to identify BPA-driven early cancer risk markers to promote translation into public health policy. The specific aims will be as follows. In aim 1, the investigators will establish a dose-response curve between chronic BPA exposure and the development of uterine atypical hyperplasia or adenocarcinoma and to determine an effective dose of BPA that will induce uterine tumor and/or hyperplasia/dysplasia in 75% of the 2-year-old rat. In aim 2, the investigators will identify BPA-associated early ECa biomarkers using an Exploration Approach, which combines genome-wide methylation promoter array analysis and global transcriptome profiling, and a Knowledge-based Approach, which selects a set of genes whose methylation status was discovered and confirmed in another ongoing study. In aim 3, the investigators will seek to determine the time course of changes of the candidate genes confirmed in aim 2 to identify the BPA-driven early uterine cancer marker genes.