Meaza Idoia, Cahill Caitlin R, Speer Rachel M, Kouokam J Calvin, Wise John Pierce
Wise Laboratory for Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, United States.
Wise Laboratory for Environmental and Genetic Toxicology, Department of Pharmacology and Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, United States.
J Hazard Mater. 2025 Mar 5;485:136892. doi: 10.1016/j.jhazmat.2024.136892. Epub 2024 Dec 15.
Hexavalent chromium [Cr(VI)] is a human lung carcinogen with widespread exposure. How Cr(VI) causes cancer is poorly understood, but chromosome instability plays a central role. Inhibition of DNA repair pathways leads to chromosome instability; however, despite the importance of these pathways in the mechanism of Cr(VI)-induced lung carcinogenesis, there are no data considering in-depth analysis on the transcriptional changes of genes involved in them. This study characterized the global transcriptional changes of mRNA expression after Cr(VI) exposure focusing on DNA repair pathways. The repair pathways considered included homologous recombination repair, non-homologous end joining, microhomology-directed end-joining, single strand annealing, mismatch repair, base excision repair, nucleotide excision repair and crosslink repair. Normal human lung fibroblast cells were exposed to increasing zinc chromate concentrations for 24, 72 or 120 h then RNA was extracted and sequenced. Our results indicate Cr(VI) causes differential expression of genes in lung cancer pathways and downregulates expression of some genes in all 8 DNA repair pathways. Homologous recombination repair, mismatch repair, base excision repair and microhomology-directed end-joining were the most affected pathways. This study provides a critical in-depth analysis of the effects of Cr(VI) on DNA repair pathways and contributes new insights into the mechanism of Cr(VI)-carcinogenesis.
六价铬[Cr(VI)]是一种广泛存在且能导致人类肺癌的致癌物。目前人们对Cr(VI)致癌的机制了解甚少，但染色体不稳定起着核心作用。DNA修复途径的抑制会导致染色体不稳定；然而，尽管这些途径在Cr(VI)诱导肺癌发生的机制中很重要，但尚无关于对其中所涉及基因转录变化进行深入分析的数据。本研究聚焦于DNA修复途径，对Cr(VI)暴露后mRNA表达的整体转录变化进行了表征。所考虑的修复途径包括同源重组修复、非同源末端连接、微同源性介导的末端连接、单链退火、错配修复、碱基切除修复、核苷酸切除修复和交联修复。将正常人肺成纤维细胞暴露于浓度不断增加的铬酸锌中24、72或120小时，然后提取RNA并进行测序。我们的结果表明，Cr(VI)会导致肺癌途径中基因的差异表达，并下调所有8种DNA修复途径中一些基因的表达。同源重组修复、错配修复、碱基切除修复和微同源性介导的末端连接是受影响最大的途径。本研究对Cr(VI)对DNA修复途径的影响进行了关键的深入分析，并为Cr(VI)致癌机制提供了新的见解。
