Chronic exposure to Biphenol A and uterine cancer risk markers

子宫内膜癌（ECa）是女性最常见的癌症。遗传学只能解释 5-10%的ECa风险，其余的则是对健康和环境的影响。观察性研究 强烈支持无对抗雌激素暴露，包括内分泌活性物质及其相关 代谢并发症与人类ECa的较高风险有关。在大鼠研究中，新生儿接触 BPA影响成年子宫对激素的反应，诱发子宫肥大、子宫增生和子宫癌。 然而，关于涉及低剂量寿命期口服暴露的更与人类相关的暴露方案的数据 是不存在的此外，其发病机制的分子机制仍然不完全 明白该项目旨在通过评估慢性低剂量辐射的影响， 双酚A（BPA）暴露对子宫增生和癌变的影响 平台我们的目标是确定BPA驱动的早期癌症风险标志物，以促进转化为公众 卫生政策。 我们的具体目标如下。在目标1中，我们将建立慢性BPA 暴露和子宫不典型增生或腺癌的发展，并确定一个 在75%的2岁大鼠中诱导子宫肿瘤和/或增生/发育不良的BPA有效剂量。 在目标2中，我们将使用探索方法鉴定BPA相关的早期ECa生物标志物， 结合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，我们选择一组基因，其甲基化状态被发现， 在另一项正在进行的研究中得到证实。在目标3中，我们将寻求确定 目标2中确认的候选基因，以鉴定BPA驱动的早期子宫癌标记基因。

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 it pathogenesis remains incompletely understood. This project aims to address these data gap gaps by assessing the impact of chronic low dose exposure to bisphenol A (BPA) on uterine hyperplasia and carcinogenesis by using a well controlled GLP platform. Our goal is to identify BPA-driven early cancer risk markers to promote translation into public health policy. Our specific aims will be as follows. In aim 1, we 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, we will identify BPA-associated eariy ECa biomarkers using an Exploration Approach, which combined genome-wide methylation promoter array analysis and global transcriptome profiling, and a Knowledge-based Approach, which we select a set of genes whose methylation status was discovered and confirmed in another ongoing study. In aim 3, we 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.