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。遗传学只能解释 5-10% 的 ECa 风险，其余则取决于荷尔蒙和环境的影响。观察性研究 强烈支持无对抗的雌激素暴露，包括内分泌活性物质及其相关物质 代谢并发症与人类较高的 ECa 风险有关。在大鼠研究中，新生儿暴露于 BPA影响成人子宫对激素的反应并诱发子宫肥大、子宫增生和癌症。 然而，有关与人类更相关的暴露方案的数据涉及低剂量寿命口服暴露 是不存在的。此外，其发病机制的分子机制仍然不完全 明白了。该项目旨在通过评估长期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 暴露双酚 A (BPA) 对子宫增生和癌变的影响 平台。我们的目标是识别 BPA 驱动的早期癌症风险标记，以促进向公众转化 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 之间的剂量反应曲线 暴露和子宫不典型增生或腺癌的发展，并确定 BPA 的有效剂量会在 75% 的 2 岁大鼠中诱发子宫肿瘤和/或增生/发育不良。 在目标 2 中，我们将使用探索方法来识别 BPA 相关的早期 ECa 生物标志物，该方法 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，我们选择一组已发现甲基化状态的基因并 另一项正在进行的研究证实了这一点。在目标 3 中，我们将寻求确定变化的时间过程。 目标 2 中确认的候选基因可识别 BPA 驱动的早期子宫癌标记基因。