PDF(Pubmed)
Abstract：
Millions of people around the world are exposed to elevated levels of arsenic through food or drinking water. Epidemiological studies have linked chronic arsenic exposure to an increased risk of several cancers, cardiovascular disease, central nervous system neuropathies, and genotoxic as well as immunotoxic effects. In addition to the induction of oxidative stress and inhibition of DNA repair processes, epigenetic effects, including altered DNA methylation patterns resulting in aberrant gene expression, may contribute to carcinogenicity. However, the underlying mechanisms by which chronic micromolar concentrations of arsenite affect the methylation status of DNA are not fully understood. In this study, human HepG2 hepatocarcinoma cells were treated with 0.5-10 μM sodium arsenite for 24 h, 10, or 20 days. During these periods, the effects on global DNA methylation, cell cycle phase distribution, and gene expression were investigated. While no impact on DNA methylation was seen after short-term exposure, global hypomethylation was observed at both long-term exposure periods, with concomitant induction of the DNA methyltransferase genes DNMT1 and DNMT3B, while DNMT3A was slightly down-regulated. Pronounced time- and concentration-dependent effects were also seen in the case of genes involved in DNA damage response and repair, inflammation, oxidative stress response, and metal homeostasis. These results suggest that chronic low-dose arsenite exposure can lead to global hypomethylation. As an underlying mechanism, the consistent down-regulation of DNA methyltransferase genes could be excluded; alternatively, interactions at the protein level could play an important role.
摘要：
世界各地有数百万人通过食物或饮用水暴露于高水平的砷。流行病学研究表明，慢性砷暴露与几种癌症的风险增加有关，心血管疾病,中枢神经系统神经病,遗传毒性和免疫毒性作用。除了诱导氧化应激和抑制DNA修复过程，表观遗传效应，包括DNA甲基化模式改变导致基因表达异常，可能导致致癌性。然而,慢性微摩尔浓度的亚砷酸盐影响DNA甲基化状态的潜在机制尚不完全清楚。在这项研究中,人HepG2肝癌细胞用0.5-10μM亚砷酸钠处理24小时，10，或20天。在这些时期,对全球DNA甲基化的影响，细胞周期相位分布，和基因表达进行了研究。虽然短期暴露后对DNA甲基化没有影响，在两个长期暴露期都观察到全球低甲基化，伴随DNA甲基转移酶基因DNMT1和DNMT3B的诱导，而DNMT3A则略有下调。在涉及DNA损伤反应和修复的基因的情况下，也可以看到明显的时间和浓度依赖性效应，炎症,氧化应激反应，和金属稳态。这些结果表明，长期低剂量亚砷酸盐暴露会导致全球低甲基化。作为一种潜在的机制，可以排除DNA甲基转移酶基因的一致下调；或者，蛋白质水平的相互作用可以发挥重要作用。
