Fetal arsenic-nutrient interaction in adult-onset cancer

描述(申请人提供)：长期目标和具体目标：我们的科学假设是，砷是一种胎儿表观诱因，母亲的脂肪营养是一种胎儿抗表观诱因，两者的平衡将决定胎儿基因沉默和成人癌症发病率。这一假设得到了以下观察结果的支持。首先，胎儿暴露在砷中对小鼠来说是一种完全的致癌物质：在子宫中短暂暴露会导致多种成人癌症。在这个模型中，砷被认为是通过耗尽甲基供体来发挥作用，导致表观遗传异常，从而促进癌症的发生。其次，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的DMA甲基化是一致的发现，表明它是致病的。第三，染砷导致小鼠肝脏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有关。第四，通过母亲的补充，胎儿暴露在饮食中的脂肪类甜菜碱、胆碱、叶酸和维生素B12中，改变了子宫中的DNA甲基化。我们建议：1.鉴定和定量胎儿砷暴露和母体膳食甲基补充剂引起的基因表达的稳定变化；2.基因差异表达与DNA甲基化缺陷的相关性；3.在有无母体甲基补充剂的情况下，评估胎儿砷暴露引起的肿瘤发病率。如果成功，我们的提议将检验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，识别对砷和饮食易感的基因，并提供一种用于量化胎儿表观遗传风险的一般筛查技术。与公共卫生相关：接触饮用水中的砷是一种已知的人类致癌物质，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，也是由于机制不明确。最近的动物研究表明，短暂的砷暴露，以及改变子宫内叶酸和B12等营养素的饮食供应，可能会影响几年后成人的癌症发病率。这项拟议的研究将调查暴露在环境毒物和宫内饮食营养之间的潜在联系，这可能会对人类癌症产生重大影响。

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.