Savery Laura C, Grlickova-Duzevik Eliza, Wise Sandra S, Thompson W Douglas, Hinz John M, Thompson Larry H, Wise John Pierce
Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, USA.
Mutat Res. 2007 Jan 10;626(1-2):120-7. doi: 10.1016/j.mrgentox.2006.09.005. Epub 2006 Nov 9.
Particulate hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Cr(VI)-induced tumors exhibit chromosome instability (CIN), but the mechanisms underlying these effects are unknown. We investigated a possible role for the Fanconi anemia (FA) pathway in particulate Cr(VI)-induced chromosomal damage by focusing on the Fancg gene, which plays an important role in cellular resistance to DNA interstrand crosslinks. We used the isogenic Chinese hamster ovary (CHO) KO40 fancg mutant compared with parental and gene-complemented cells. We found that fancg cells treated with lead chromate had lower intracellular Cr ion levels than control cell lines. Accounting for differences of Cr ion levels between cell lines, we discovered that fancg cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, which was not observed after restoring the Fancg gene. Chromosomal damage was manifest as increased total chromosome damage and percent metaphases with damage, specifically an increase in chromatid and isochromatid breaks. We conclude that Fancg protects cells from particulate Cr(VI)-induced cytotoxicity and chromosome damage, which is consistent with the known sensitivity of fancg cells to crosslinking damage and the ability of Cr(VI) to produce crosslinks.
颗粒状六价铬（Cr(VI)）是一种已知的人类肺癌致癌物。Cr(VI)诱导的肿瘤表现出染色体不稳定性（CIN），但其潜在机制尚不清楚。我们通过聚焦在细胞对DNA链间交联的抗性中起重要作用的Fancg基因，研究了范可尼贫血（FA）途径在颗粒状Cr(VI)诱导的染色体损伤中的可能作用。我们使用了同基因的中国仓鼠卵巢（CHO）KO40 fancg突变体，并与亲本细胞和基因互补细胞进行比较。我们发现，用铬酸铅处理的fancg细胞的细胞内Cr离子水平低于对照细胞系。考虑到细胞系之间Cr离子水平的差异，我们发现用铬酸铅处理的fancg细胞的细胞毒性和染色体畸变增加，而在恢复Fancg基因后未观察到这种情况。染色体损伤表现为总染色体损伤增加和有损伤的中期百分比增加，特别是染色单体和等臂染色单体断裂增加。我们得出结论，Fancg保护细胞免受颗粒状Cr(VI)诱导的细胞毒性和染色体损伤，这与已知的fancg细胞对交联损伤的敏感性以及Cr(VI)产生交联的能力一致。
