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. Additonally, the molecular mechanisms underiying it 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. Oure goal is to identify BPA-driven eariy 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 eariy uterine cancer marker genes.
The result obtained from uterus will define a set of epigenetic predictor genes in which eariy-life exposure of BPA interact with later-life event to bring out an adverse phenotype. The result from the chronic and lifelong exposure of BPA provides a framework for using epigenetic and other biomarkers in translating results from animal models of pollutant exposures to human studies for the development of personalized prevention and intervention.
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