Fetal arsenic-nutrient interaction in adult-onset cancer

成人发病癌症中胎儿砷与营养素的相互作用

• 批准号: 7039311
• 负责人: Kenneth B Beckman
• 金额: $ 20.01万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039311
• 关键词: DNA methylation; antineoplastics; arsenic; betaine compound; cancer risk; carcinogen testing; carcinogens; choline; dietary supplements; differential display technique; disease /disorder onset; embryo /fetus toxicology; environment related neoplasm /cancer; environmental exposure; epigenetics; folate; gene expression profiling; gene induction /repression; genetic susceptibility; laboratory mouse; mother /embryo /fetus nutrition; mutagens; neoplasm /cancer epidemiology; nutrient interaction; nutrition related tag; technology /technique development; vitamin B12

DESCRIPTION (provided by applicant): LONG-TERM OBJECTIVES AND SPECIFIC AIMS: Our scientific hypothesis is that arsenic is a fetal epimutagen, maternal lipotropic nutrition a fetal anti-epimutagen, and that the balance of the two will determine fetal gene silencing and adult-onset cancer incidence. This hypothesis is supported by the following observations. First, fetal exposure to arsenic is a complete carcinogen in mice: a brief exposure in utero results in multiple adult-onset cancers. In this model, arsenic has been proposed to act by depleting methyl donors, resulting in epigenetic aberrations that contribute to carcinogenesis. Second, in rodent models of methyl deficiency-induced hepatocellular carcinoma, altered global and gene-specific DMA methylation was a consistent finding, suggesting that it was causative. Third, arsenic administration causes global and gene-specific hypomethylation of liver DNA in mice that is correlated with differential expression of affected genes. Fourth, fetal exposure to the dietary lipotropes betaine, choline, folate and vitamin B12, through maternal supplementation, alters DNA methylation in utero. We propose to: 1. identify and quantitate stable changes in gene expression caused by fetal exposure to arsenic and maternal dietary methyl supplementation, 2. correlate differential expression of genes with defects in DNA methylation, and 3. evaluate tumor incidence resulting from fetal arsenic exposure in the presence and absence of maternal methyl supplementation. If successful, our proposal will test the theory that arsenic is an epimutagen, test the theory that nutrients are anti-epimutagens, identify genes that are susceptible to arsenic and diet, and provide a general screening technique for use in quantifying fetal epigenetic risks. PUBLIC HEALTH RELEVANCE: exposure to arsenic in drinking water is a known human carcinogen, yet its mechanism of action is not well understood. Poor nutrition is also a key risk factor for cancer in humans, also by poorly defined mechanisms. Recent animal studies suggest that brief exposure to arsenic, and altered dietary supply of nutrients such as folate and B12 in the womb, may influence cancer incidence years later, in adults. The proposed research will investigate the potential links between exposure to environmental toxicants and dietary nutrition in utero that may contribute significantly to human cancer.

描述（由申请人提供）：长期毒性和特定目的：我们的科学假设是砷是胎儿表突变原，母体亲脂营养是胎儿抗表突变原，两者的平衡将决定胎儿基因沉默和成人发病癌症的发生率。这一假设得到以下观察结果的支持。首先，胎儿暴露于砷是一个完整的致癌物质在小鼠：在子宫内的短期接触导致多种成人发病的癌症。在这个模型中，砷被认为是通过消耗甲基供体而起作用的，从而导致导致致癌作用的表观遗传畸变。第二，在甲基缺乏诱导的肝细胞癌的啮齿动物模型中，改变的全局和基因特异性DMA甲基化是一致的发现，表明它是病因。第三，砷管理导致全球和基因特异性低甲基化的小鼠肝脏DNA与受影响的基因的差异表达。第四，胎儿暴露于饮食中的脂肪细胞甜菜碱，胆碱，叶酸和维生素B12，通过母亲的补充，改变DNA甲基化在子宫内。我们建议：1.鉴定和定量由胎儿暴露于砷和母体膳食甲基补充剂引起的基因表达的稳定变化，2.将基因的差异表达与DNA甲基化缺陷相关联，以及3.评估在母亲补充甲基和不补充甲基的情况下胎儿砷暴露导致的肿瘤发病率。如果成功的话，我们的提案将测试砷是表观诱变剂的理论，测试营养素是抗表观诱变剂的理论，识别对砷和饮食敏感的基因，并提供一种用于量化胎儿表观遗传风险的通用筛选技术。公共卫生相关性：暴露于饮用水中的砷是一种已知的人类致癌物，但其作用机制尚不清楚。营养不良也是人类癌症的一个关键风险因素，也是由不明确的机制引起的。最近的动物研究表明，在子宫内短暂接触砷，以及改变膳食中叶酸和B12等营养物质的供应，可能会影响成年人多年后的癌症发病率。拟议的研究将调查暴露于环境毒物和子宫内饮食营养之间的潜在联系，这可能会显着促进人类癌症。