Cheng L, Liu S, Dixon K
Department of Internal Medicine, Emory University, Grey Memorial Hospital, Atlanta, Georgia, USA.
Environ Health Perspect. 1998 Aug;106 Suppl 4(Suppl 4):1027-32. doi: 10.1289/ehp.98106s41027.
Chromium (Cr) is a widespread environmental contaminant and a known human carcinogen. We have used shuttle vector systems in yeast, mammalian cells, and transgenic mice to characterize the mutational specificity and premutational DNA damage induced by Cr(VI) and its reduction intermediates in order to elucidate the mechanism by which Cr induces mutations. In the yeast system, treatment of vector-containing cells with Cr(VI) results in a dose-dependent increase in mutations in the SUP4-o target gene of the vector; mutagenesis is enhanced in an apn-1 yeast mutant, deficient in the capacity to repair oxidative-type DNA damage. In vector-containing mammalian cells, treatment with Cr(VI) also results in a dose-dependent increase in mutations in the vector target gene supF. The Cr-induced mutations in supF occurred mostly at G:C base pairs and were widely distributed across the gene, a pattern similar to those observed with ionizing radiation or hydrogen peroxide. These results support the hypothesis that Cr(VI)-induced oxidative-type DNA damage is responsible for Cr mutagenesis in the cell. Recently these studies were extended into the Big Blue transgenic mouse system in which Cr-induced mutagenesis was observed in the lung, the target organ for Cr carcinogenesis in humans. Analysis of the spectrum of these mutations will test whether Cr mutagenesis occurs by similar mechanisms in the intact animal as in cell culture systems and yeast.
铬（Cr）是一种广泛存在的环境污染物，也是一种已知的人类致癌物。我们利用酵母、哺乳动物细胞和转基因小鼠中的穿梭载体系统来表征六价铬（Cr(VI)）及其还原中间体诱导的突变特异性和突变前DNA损伤，以阐明铬诱导突变的机制。在酵母系统中，用Cr(VI)处理含载体的细胞会导致载体的SUP4-o靶基因中的突变呈剂量依赖性增加；在缺乏修复氧化型DNA损伤能力的apn-1酵母突变体中，诱变作用增强。在含载体的哺乳动物细胞中，用Cr(VI)处理也会导致载体靶基因supF中的突变呈剂量依赖性增加。Cr诱导的supF突变大多发生在G:C碱基对处，并且在整个基因中广泛分布，这种模式类似于电离辐射或过氧化氢所观察到的模式。这些结果支持了这样的假设，即Cr(VI)诱导的氧化型DNA损伤是细胞中铬诱变的原因。最近，这些研究扩展到了“大蓝”转基因小鼠系统，在该系统中，在肺中观察到了铬诱导的诱变，肺是人类铬致癌作用的靶器官。对这些突变谱的分析将检验铬诱变在完整动物中是否通过与细胞培养系统和酵母中类似的机制发生。
