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）：长期目标和具体目标：我们的科学假设是，砷是胎儿表观诱变剂，母体亲脂性营养是胎儿抗表观诱变剂，两者的平衡将决定胎儿基因沉默和成人-癌症发病率。该假设得到以下观察结果的支持。首先，胎儿接触砷对小鼠来说是一种完全致癌物：子宫内短暂接触砷会导致多种成年癌症。在该模型中，砷被认为通过消耗甲基供体而发挥作用，导致表观遗传畸变，从而导致致癌。其次，在甲基缺乏诱发的肝细胞癌的啮齿动物模型中，一致的发现是整体和基因特异性 DMA 甲基化的改变，表明这是致病因素。第三，砷施用会导致小鼠肝脏 DNA 的整体和基因特异性低甲基化，这与受影响基因的差异表达相关。第四，通过母体补充，胎儿接触膳食抗脂剂甜菜碱、胆碱、叶酸和维生素 B12，会改变子宫内的 DNA 甲基化。我们建议：1. 识别和定量因胎儿暴露于砷和母亲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. 评估胎儿砷暴露导致的肿瘤发生率在存在或不存在母体甲基补充剂的情况下。如果成功，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，并提供用于量化胎儿表观遗传风险的通用筛查技术。公共健康相关性：接触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。营养不良也是人类患癌症的一个关键危险因素，其机制也不明确。最近的动物研究表明，短暂接触砷以及改变子宫内叶酸和维生素 B12 等营养物质的饮食供应可能会影响数年后成人癌症的发病率。拟议的研究将调查环境毒物暴露与子宫内膳食营养之间的潜在联系，这可能对人类癌症产生重大影响。