Chronic exposure to Biphenol A and uterine cancer risk markers

长期接触双酚 A 和子宫癌风险标志物

• 批准号: 8686853
• 负责人: Shuk-Mei Ho
• 金额: $ 27.2万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686853
• 关键词: 2 year old; Accounting; Address; Adenocarcinoma; Adult; Affect; Aging; Animal Model; Apoptosis; Area; Atypical hyperplasia; Biological Markers; Candidate Disease Gene; Cell Proliferation; Chronic; Data; Data Set; Detection; Development; Dose; Dysplasia; Elderly; Endocrine; Endometrial Carcinoma; Epigenetic Process; Epithelial Cells; Estradiol; Estrogens; Estrone; Event; Exposure to; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Health Policy; Hormone replacement therapy; Hormones; Human; Hyperplasia; In Situ; Instruction; Intake; Intervention; Lasers; Life; Link; Longevity; Malignant Neoplasms; Measurement; Metabolic; Metabolic Diseases; Methylation; Molecular; Monitor; Observational Study; Oral; Ovarian hormone; Ovariectomy; Pathogenesis; Phenotype; Postmenopause; Predisposition; Pregnancy; Preventive Intervention; Prostate; Protocols documentation; Public Health; Rattus; Regimen; Reporting; Research; Rest; Risk Marker; Rodent; Time; Time Study; Tissues; Translating; Translations; Uterine Cancer; Uterine Neoplasms; Uterus; Validation; Vertebral column; Woman; base; bisphenol A; bisulfite; cancer diagnosis; cancer risk; carcinogenesis; early life exposure; epigenetic marker; genome wide methylation; high risk; knowledge base; methylome; neonatal exposure; pollutant; promoter; protein expression; pyrosequencing; response

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.

子宫内膜癌（ECa）是女性中最常见的癌症。基因只能解释