Arsenic mode of action in cancer--Models of epigenic mechanism

砷给环境健康科学家带来了独特的问题，因为它被认为是人类致癌物，但在动物模型中不致癌。此外，砷化合物不诱导基因突变，尽管它们确实增强了其他诱变剂的遗传毒性效应，并与染色体异常有关。这些性质表明，砷的作用模式不同于其他特征明确的环境致癌物，其作用是由DNA损伤介导的。一种假设是砷通过表观遗传机制起作用;砷可能产生可逆的细胞改变，影响参与生长和分化的基因的表达。本提案的目的是在一项正在进行的基于人群的膀胱癌病例对照研究的背景下调查砷暴露的影响。我们假设，在疾病的因果通路中的基因的DNA甲基化将发生在膀胱癌的情况下，谁也暴露于高水平的砷剂的频率更高。因此，我们建议调查甲基化和突变的基因在膀胱癌的发生的因果途径，特别注意它们与砷暴露的关联。

Arsenic poses unique problems for environmental health scientists in that it is recognized as a human carcinogenic but is not carcinogenic in animal models. Furthermore, arsenical compounds do not induce gene mutations, although they do potentiate the genotoxic effects of other mutagens and are associated with chromosomal abnormalities. These properties indicate that arsenic has a mode of action different from other well-characterized environmental carcinogens whose actions are mediated by DNA damage. One hypothesis is that arsenic acts through epigenetic mechanisms; arsenic may produce reversible cell alterations that influence the expression of genes involved in growth and differentiation. The purpose of this proposal is to investigate the effects of arsenic exposure in the context of an ongoing population based case control study of bladder cancer. We hypothesize that DNA methylation of genes in the causal pathway for disease will occur with a higher frequency in cases with bladder cancer who are also exposed to high levels of arsenicals. Thus, we propose to investigate methylation and mutation of genes in the causal pathway for the genesis of bladder cancer, with special attention to their association with exposure to arsenic.