首页> 美国卫生研究院文献>Environmental Health Perspectives >Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species.
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Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species.

机译:青石棉石棉在哺乳动物细胞中的遗传毒性机理:由活性氧诱导的突变模式的影响。

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摘要

Asbestos is an important environmental carcinogen in the United States and remains the primary occupational concern in many developing countries; however, the underlying mechanisms of its genotoxicity are not known. We showed previously that asbestos is a potent gene and chromosomal mutagen in mammalian cells and that it induces mostly multilocus deletions. Furthermore, reactive oxygen species (ROS) are associated with the mutagenic process. To evaluate the contribution of ROS to the mutagenicity of asbestos, we examined their generation, particularly hydrogen peroxide, and compared the types of mutants induced by crocidolite fibers with those generated by H(2)O(2 )in human-hamster hybrid (A(L)) cells. Using confocal scanning microscopy together with the radical probe 5,6 -chloromethy-2,7 -dichlorodihydrofluorescein diacetate (CM-H(2)DCFDA), we found that asbestos induces a dose-dependent increase in the level of ROS among fiber-treated A(L) cells, which is suppressed by concurrent treatment with dimethyl sulfoxide. Using N-acetyl-3,7-dihydroxyphenoxazine (Amplex Red reagent) together with horseradish peroxidase, we further demonstrated that there was a dose-dependent induction of H(2)O(2) in crocidolite-treated A(L) cells. The amount of H(2)O(2 )induced by asbestos reached a plateau at a dose of 6 microg/cm(2). Concurrent treatment with catalase (1,000 U/mL) inhibited this induction by 7- to 8-fold. Mutation spectrum analysis showed that the types of CD59(-) mutants induced by crocidolite fibers were similar to those induced by equitoxic doses of H(2)O(2). These results provide direct evidence that the mutagenicity of asbestos is mediated by ROS in mammalian cells.
机译:石棉在美国是一种重要的环境致癌物质,在许多发展中国家仍然是主要的职业问题;然而,其遗传毒性的潜在机制尚不清楚。先前我们已经证明,石棉是哺乳动物细胞中的有效基因和染色体诱变剂,并且它主要诱导多位点缺失。此外,活性氧(ROS)与诱变过程有关。为了评估ROS对石棉致突变性的贡献,我们检查了它们的生成,特别是过氧化氢,并比较了青石棉纤维诱导的突变体类型与人仓鼠杂种中H(2)O(2)产生的突变体类型(A (L))个单元格。使用共聚焦扫描显微镜和自由基探针5,6-氯代甲基-2,7-二氯二氢荧光素二乙酸酯(CM-H(2)DCFDA),我们发现石棉在纤维处理的ROS中引起剂量依赖性的ROS升高。 A(L)细胞,可通过同时使用二甲基亚砜来抑制。使用N-乙酰基3,7-二羟基苯恶嗪(Amplex Red试剂)与辣根过氧化物酶,我们进一步证明在青石棉处理过的A(L)细胞中存在H(2)O(2)的剂量依赖性诱导。由石棉诱导的H(2)O(2)的量达到了6 microg / cm(2)的稳定水平。过氧化氢酶(1,000 U / mL)的同时处理将这种诱导抑制了7到8倍。突变谱分析表明,青石棉纤维诱导的CD59(-)突变体的类型与等毒性剂量的H(2)O(2)诱导的类型相似。这些结果提供了直接的证据,表明在哺乳动物细胞中,石棉的致突变性是由ROS介导的。

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