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）是女性最常见的癌症。遗传学只能说明 ECA风险的5-10％在于荷尔蒙和环境影响。观察性研究 强烈支持无反对的雌激素暴露，包括内分泌活性物质及其相关物质 代谢并发症与人类ECA风险更高有关。在大鼠研究中，新生儿暴露于 BPA影响成年子宫对激素的反应和诱导的子宫植物，子宫增生和癌症。 但是，有关涉及低剂量寿命的更相关暴露方案的数据 不存在。此外，发病机理的基础机制仍然不完全 理解。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 通过使用良好控制的GLP，在子宫增生和癌变上暴露于双酚A（BPA）（BPA） 平台。我们的目标是确定BPA驱动的早期癌症风险标志物，以促进公开翻译 卫生政策。 我们的具体目标如下。在AIM 1中，我们将在慢性BPA之间建立剂量反应曲线 暴露与子宫非典型增生或腺癌的发展，并确定 有效剂量的BPA会诱导子宫肿瘤和/或增生/或增生/或增生性剂量，其中75％的2岁大鼠。 在AIM 2中，我们将使用勘探方法来识别与BPA相关的ECA ECA生物标志物，该方法 全基因组甲基化启动子阵列分析和全局转录组分析和A组合 基于知识的方法，我们选择了一组发现的基因，其甲基化状态被发现并 在另一项正在进行的研究中得到证实。在AIM 3中，我们将寻求确定变化的时间过程 AIM 2中证实的候选基因以鉴定BPA驱动的早期子宫癌标记基因。