Linking arsenite- and cadmium-generated oxidative stress to microsatellite instability in vitro and in vivo

• Published in: Free radical biology & medicine Vol. 112; pp. 12 - 23
• Main Authors: Wu, Chang-Lin, Huang, Li-Yan, Chang, Christina L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2017
• Subjects: Acetylcysteine - pharmacology; Animals; Antioxidants; Antioxidants - pharmacology; Arsenic; Arsenites - antagonists & inhibitors; Arsenites - toxicity; Cadmium; Cadmium Chloride - antagonists & inhibitors; Cadmium Chloride - toxicity; Cell Line, Tumor; Cell Survival - drug effects; DNA - genetics; DNA - metabolism; DNA Damage; DNA Mismatch Repair - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Free radicals; Gene Expression Regulation; Genes, Reporter; HCT116 Cells; Humans; Microsatellite instability; Microsatellite Instability - drug effects; Microsatellite Repeats - drug effects; Mismatch repair; MutL Protein Homolog 1 - genetics; MutL Protein Homolog 1 - metabolism; MutS Homolog 2 Protein - genetics; MutS Homolog 2 Protein - metabolism; Oxidative Stress; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Sodium Compounds - antagonists & inhibitors; Sodium Compounds - toxicity; Zebrafish; Cd; RS; Cadmium; Oxidative stress; MSI; Free radicals; Arsenic; AsV; 8-oxoG; Microsatellite instability; MSS; Antioxidants; NAC; DDR; MMR; RNS; Mismatch repair; ROS; GSH; AsIII; Hpf; 8-OHdG
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.07.006

Mismatch repair (MMR) corrects replicative errors and minimizes DNA damage that occurs frequently in microsatellites. MMR deficiency is manifested as microsatellite instability (MSI), which contributes to hypermutability and cancer pathogenesis. Genomic instability, including MSI and chromosomal instability, appears to be responsible for the carcinogenesis of arsenic and cadmium, common contaminants in our environment. However, few studies have addressed arsenic- or cadmium-induced MSI, especially its potential link with arsenic- or cadmium-generated oxidative stress, due to the lack of quantifiable MSI assays and cost-effective animal models. Here, using a dual-fluorescent reporter, we demonstrate that sub-lethal doses of cadmium or arsenite, but not arsenate, increased the MSI frequency in human colorectal cancer cells. Arsenite- and cadmium-induced MSI occurred concomitantly with increased levels of reactive species and oxidative DNA damage, and with decreased levels of MMR proteins. However, N-acetyl-l-cysteine (NAC) suppressed arsenite- and cadmium-induced MSI and oxidative stress while restoring the levels of MMR proteins in the cells. Similarly, MSI was induced separately by arsenite and cadmium, and suppressed by NAC, in zebrafish in a fluorescinated PCR-based assay with newly-developed microsatellite markers and inter-segmental comparisons. Of five selected antioxidants examined, differential effects were exerted on the MSI induction and cytotoxicity of both arsenite and cadmium. Compared to MMR-proficient cells, MMR-deficient cells were more resistant to arsenic-mediated and cadmium-mediated cytotoxicity. Our findings demonstrate a novel linkage between arsenite-generated and cadmium-generated oxidative stress and MSI induction. Our findings also caution that antioxidants must be individually validated before being used for preventing arsenite- and cadmium-induced MSI that is associated with cancer development. •Arsenite and cadmium induce microsatellite instability (MSI) in vitro and in vivo.•Arsenite (As)- and cadmium (Cd)-induced oxidative stress is linked to MSI induction.•Mismatch repair (MMR) deficiency increases resistance to arsenite or cadmium.•Differential effects of antioxidants on MSI induction & cytotoxicity of As or Cd.•New microsatellite markers and analysis strategy for detecting MSI in zebrafish. [Display omitted]