Browning Cynthia L, Wise Catherine F, Wise John Pierce
Wise Laboratory of Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville School of Medicine, 505 S Hancock St, CTRB, Louisville, KY 40292, USA; Graduate School of Biomedical Science and Engineering, University of Maine, 42 Stodder Hall, Orono, ME 04469, USA.
Program in Environmental and Molecular Toxicology, Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, USA.
Toxicol Appl Pharmacol. 2017 Sep 15;331:18-23. doi: 10.1016/j.taap.2017.04.006. Epub 2017 Apr 11.
Chromosome instability is a common feature of cancers that forms due to the misrepair of DNA double strand breaks. Homologous recombination (HR) repair is a high fidelity DNA repair pathway that utilizes a homologous DNA sequence to accurately repair such damage and protect the genome. Prolonged exposure (>72h) to the human lung carcinogen, particulate hexavalent chromium (Cr(VI)), inhibits HR repair, resulting in increased chromosome instability in human cells. Comparative studies have shown acute Cr(VI) exposure induces less chromosome damage in whale cells than human cells, suggesting investigating the effect of this carcinogen in other species may inform efforts to prevent Cr(VI)-induced chromosome instability. Thus, the goal of this study was to determine the effect of prolonged Cr(VI) exposure on HR repair and clastogenesis in North Atlantic right whale (Eubalaena glacialis) lung cells. We show particulate Cr(VI) induces HR repair activity after both acute (24h) and prolonged (120h) exposure in North Atlantic right whale cells. Although the RAD51 response was lower following prolonged Cr(VI) exposure compared to acute exposure, the response was sufficient for HR repair to occur. In accordance with active HR repair, no increase in Cr(VI)-induced clastogenesis was observed with increased exposure time. These results suggest prolonged Cr(VI) exposure affects HR repair and genomic stability differently in whale and human lung cells. Future investigation of the differences in how human and whale cells respond to chemical carcinogens may provide valuable insight into mechanisms of preventing chemical carcinogenesis.
染色体不稳定是癌症的一个常见特征,它是由于DNA双链断裂修复错误而形成的。同源重组(HR)修复是一种高保真的DNA修复途径,它利用同源DNA序列来准确修复此类损伤并保护基因组。长时间暴露(>72小时)于人类肺癌致癌物——颗粒状六价铬(Cr(VI))会抑制HR修复,导致人类细胞中染色体不稳定性增加。比较研究表明,急性暴露于Cr(VI)时,鲸鱼细胞中的染色体损伤比人类细胞少,这表明研究这种致癌物在其他物种中的作用可能有助于预防Cr(VI)诱导的染色体不稳定。因此,本研究的目的是确定长时间暴露于Cr(VI)对北大西洋露脊鲸(Eubalaena glacialis)肺细胞中HR修复和染色体断裂的影响。我们发现,颗粒状Cr(VI)在急性(24小时)和长时间(120小时)暴露后均可诱导北大西洋露脊鲸细胞中的HR修复活性。虽然长时间暴露于Cr(VI)后的RAD51反应比急性暴露时低,但该反应足以使HR修复发生。与活跃的HR修复一致,未观察到随着暴露时间增加Cr(VI)诱导的染色体断裂增加。这些结果表明,长时间暴露于Cr(VI)对鲸鱼和人类肺细胞中HR修复和基因组稳定性的影响不同。未来对人类和鲸鱼细胞对化学致癌物反应差异的研究可能会为预防化学致癌作用的机制提供有价值的见解。