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，其余的风险在于激素和环境影响。观察性研究 强烈支持非竞争性雌激素暴露，包括内分泌活性物质及其相关物质 代谢并发症与人类更高的ECA风险有关。在老鼠研究中，新生儿暴露于 双酚A影响成人子宫对激素的反应，并诱导子宫肥大、子宫增生和癌症。 然而，关于一种与人类更相关的暴露方案的数据，涉及到低剂量的终身口服暴露 是不存在的。此外，其发病的分子机制尚不完全清楚。 明白了。该项目旨在通过评估慢性低剂量的影响来解决这些数据差距 应用控制良好的GLP研究双酚A(BPA)对子宫增生和癌变的影响 站台。我们的目标是确定双酚A驱动的早期癌症风险标记物，以促进转化为公众 健康政策。 我们的具体目标如下。在目标1中，我们将建立慢性双酚A之间的剂量-反应曲线 子宫不典型增生或腺癌的暴露和发展，并确定 有效剂量的双酚A将导致75%的2岁大鼠子宫肿瘤和/或增生/异型增生。 在目标2中，我们将使用一种探索方法来识别与BPA相关的早期ECA生物标记物，该方法 结合全基因组甲基化启动子阵列分析和全球转录组分析，以及 基于知识的方法，我们选择一组甲基化状态已被发现的基因，并 在另一项正在进行的研究中证实了这一点。在目标3中，我们将设法确定 在AIM 2中确认的候选基因用于鉴定双酚A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.