Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America; Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America; Department of Applied Medical Science, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, United States of America.
Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America; Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America.
Mutat Res. 2014 Apr;762:1-9. doi: 10.1016/j.mrfmmm.2014.02.001. Epub 2014 Feb 19.
Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive. DU is genotoxic, inducing DNA double strand breaks, chromosome damage and mutations, but the mechanisms of genotoxicity or repair pathways involved in protecting cells against DU-induced damage remain unknown. The purpose of this study was to investigate the effects of homologous recombination repair deficiency on DU-induced genotoxicity using RAD51D and XRCC3-deficient Chinese hamster ovary (CHO) cell lines. Cells deficient in XRCC3 (irs1SF) exhibited similar cytotoxicity after DU exposure compared to wild-type (AA8) and XRCC3-complemented (1SFwt8) cells, but DU induced more break-type and fusion-type lesions in XRCC3-deficient cells compared to wild-type and XRCC3-complemented cells. Surprisingly, loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. DU induced selective X-chromosome fragmentation irrespective of RAD51D status, but loss of XRCC3 nearly eliminated fragmentation observed after DU exposure in wild-type and XRCC3-complemented cells. Thus, XRCC3, but not RAD51D, protects cells from DU-induced breaks and fusions and also plays a role in DU-induced chromosome fragmentation.
贫铀（DU）在工业和军事应用中都被广泛使用。民用和军事人员接触 DU 的可能性正在增加，但关于 DU 暴露的潜在健康危害的数据有限。先前的实验室研究表明，DU 是一种潜在的致癌物质，但流行病学研究仍不确定。DU 具有遗传毒性，可诱导 DNA 双链断裂、染色体损伤和突变，但遗传毒性的机制或参与保护细胞免受 DU 诱导损伤的修复途径尚不清楚。本研究旨在使用 RAD51D 和 XRCC3 缺陷型中国仓鼠卵巢（CHO）细胞系研究同源重组修复缺陷对 DU 诱导的遗传毒性的影响。与野生型（AA8）和 XRCC3 互补（1SFwt8）细胞相比，XRCC3 缺陷型（irs1SF）细胞在 DU 暴露后表现出相似的细胞毒性，但与野生型和 XRCC3 互补细胞相比，DU 诱导 XRCC3 缺陷型细胞产生更多的断裂型和融合型损伤。令人惊讶的是，RAD51D 的缺失并不影响 DU 诱导的细胞毒性或遗传毒性。DU 诱导了 X 染色体的选择性片段化，而与 RAD51D 状态无关，但 XRCC3 的缺失几乎消除了在野生型和 XRCC3 互补细胞中 DU 暴露后观察到的片段化。因此，XRCC3 而不是 RAD51D 可保护细胞免受 DU 诱导的断裂和融合，并且还在 DU 诱导的染色体片段化中发挥作用。
