Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations
Arsenite induces delayed mutagenesis and transformation in human osteosarcoma cells at extremely low concentrations
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DOI：
10.1002/em.10164
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发表时间：
2003-01-01
影响因子：
2.8
通讯作者：
Rossman, TG
中科院分区：
文献类型：
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作者：
Mure, K;Uddin, AN;Rossman, TG
亚砷酸盐是一种人类多部位致癌物质，但其作用机制尚不清楚。我们最近发现，极低浓度(小于或等于0.1um)的亚砷酸盐可以将人骨肉瘤TE85(HOS)细胞转化为贴壁独立的细胞。与其他致癌物在暴露几天内转化这些细胞不同，亚砷酸盐暴露近8周才能转化。我们决定在我们之前开发的自发诱变试验中使用长期暴露来重新检查亚砷酸盐的致突变性问题。亚砷酸盐在极低浓度(小于或等于0.1微米)时能以剂量依赖的方式引起延迟的诱变增加。突变频率的增加发生在亚砷酸盐生长了近20代之后。变形需要30多代的连续曝光。我们还发现亚砷酸盐以剂量依赖的方式诱导二氢叶酸还原酶(DHFR)基因的扩增。由于HOS细胞能够以很低的速度甲基化亚砷酸盐，可能是活性代谢产物如单甲基亚砷酸(MMA(III))导致了这些细胞的延迟突变和转化。然而，当用MMA(III)重复检测时，我们没有发现突变或转化的显著增加，这表明亚砷酸盐诱导的延迟突变和转化不是由亚砷酸盐的代谢产物引起的，而是由亚砷酸盐本身引起的。我们的结果表明，长期暴露于低浓度亚砷酸盐可能会影响导致进行性基因组不稳定的信号通路。(C)2003年Wiley-Liss，Inc.
Arsenite is a human multisite carcinogen, but its mechanism of action is not known. We recently found that extremely low concentrations (less than or equal to0.1 muM) of arsenite transform human osteosarcoma TE85 (HOS) cells to anchorage-independence. In contrast to other carcinogens which transform these cells within days of exposure, almost 8 weeks of arsenite exposure are required for transformation. We decided to reexamine the question of arsenite mutagenicity using chronic exposure in a spontaneous mutagenesis assay we previously developed. Arsenite was able to cause a delayed increase in mutagenesis at extremely low concentrations (less than or equal to0.1 muM) in a dose-dependent manner. The increase in mutant frequency occurred after almost 20 generations of growth in arsenite. Transformation required more than 30 generations of continuous exposure. We also found that arsenite induced gene amplification of the dihydrofolate reductase (DHFR) gene in a dose-dependent manner. Since HOS cells are able to methylate arsenite at a very low rate, it was possible that active metabolites such as monomethylarsonous acid (MMA(III)) contributed to the delayed mutagenesis and transformation in these cells. However, when the assay was repeated with MMA(III), we found no significant increase in mutagenesis or transformation, suggesting that arsenite-induced delayed mutagenesis and transformation are not caused by arsenite's metabolites, but by arsenite itself. Our results suggest that long-term exposure to low concentrations of arsenite may affect signaling pathways that result in a progressive genomic instability. (C) 2003 Wiley-Liss, Inc.