Nutritional Influences on Aresenic Toxicity

描述（申请人提供）：目前已知的最大规模砷暴露是由于恒河-雅鲁藏布江三角洲地区的地下水污染造成的。从砷暴露到砷中毒临床表现的易感性存在显著的个体间差异。（例如皮肤癌、肺癌、肝癌和膀胱癌）几项观察性和生物化学研究已经导致了一种流行的假设，即营养状况可能是这种变异性的很大一部分，虽然没有对照临床研究已经解决了这个重要的假设。无机砷（InAs）的甲基化通常被认为是一种解毒途径InAs和DNA都通过一碳代谢甲基化，一种依赖于叶酸从头产生一碳基团的生化途径，并且还使用维生素B12和B6作为辅因子。该提议的主要假设是一碳代谢的营养调节，特别是叶酸的可用性，大大有助于在InAs和DNA甲基化中观察到的大的个体间变异性，从而从砷暴露到毒性的进展这一假设将首先在孟加拉国长期暴露于砷污染的饮用水的成人和儿童的横断面研究中进行测试。也被认为可能影响从砷暴露到毒性的进展，尽管这些相互作用的机制基础还不太清楚。探索性研究将把这些可能性作为儿童的次要目标，他们更可能缺乏这些营养素。第三个目标将测试，在成人或儿童中，砷暴露与淋巴细胞DNA低甲基化有关，这是某些癌症的早期事件。最后，将对血浆同型半胱氨酸浓度升高和血浆叶酸浓度低的成人进行为期12周的双盲安慰剂对照叶酸补充试验，以确定叶酸补充是否会改善砷和/或淋巴细胞DNA甲基化。

DESCRIPTION (provided by applicant): The largest known mass exposure to arsenic is presently occurring due to ground water contamination of well water throughout the Ganges-Brahmaputra Delta There is significant inter-individual variability in susceptibility to progression from arsenic exposure to clinical manifestations of arsenic toxicity (e g skin, lung, liver and bladder cancers) Several observational as well as biochemical studies have led to a prevalent hypothesis that nutritional status may account for a substantial portion of this variability, though no controlled clinical studies have addressed this important hypothesis. Methylation of inorganic arsenic (InAs) is generally considered to be a detoxification pathway InAs and DNA are both methylated via one-carbon metabolism, a biochemical pathway which is dependent on folate for de novo generation of one-carbon groups, and also uses vitamins B12 and B6 as cofactors The primary hypothesis of this proposal is that nutritional regulation of one-carbon metabolism, specifically folate availability, contributes substantially to the large inter-individual variability observed in InAs and DNA methylation, and thus progression from arsenic exposure to toxicity This hypothesis will first be tested in cross-sectional studies of adults and children chronically exposed to arsenic-contaminated drinking water in Bangladesh Other nutritional deficiencies, including those of retinol, carotenoids and protein, have also been implicated as possibly influencing progression from arsenic exposure to toxicity, although the mechanistic bases for these interactions are somewhat less clear Exploratory studies will address these possibilities as secondary objectives in children, who are more likely to be deficient in these nutrients A third objective will test whether, in adults or children, arsenic exposure is correlated with lymphocyte DNA hypomethylation, an early event in some cancers. Finally, a 12-week double blind placebo controlled folate supplementation trial of adults with elevated plasma homocysteine concentrations and low plasma folate concentrations will be conducted to determine if folate supplementation results in improved arsenic and/or lymphocyte DNA methylation.