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Although it is widely known that arsenic-contaminated drinking water causes many diseases, arsenic's exact mode of action (MOA) is not fully understood. Induction of oxidative stress has been proposed as an important key event in the toxic MOA of arsenic. The authors' studies are centered on identifying a reactive species involved in the genotoxicity of arsenic using a catalase (CAT) knockout mouse model that is impaired in its ability to breakdown hydrogen peroxide (H2O2). The authors assessed the induction of DNA damage using the Comet assay following exposure of mouse Cat+/+ and Cat-/- primary splenic lymphocytes to monomethylarsonous acid (MMAIII) to identify the potential role of H2O2 in mediating cellular effects of this metalloid. The results showed that the Cat-/- lymphocytes are more susceptible to MMAIII than the Cat+/+ lymphocytes by a small (1.5-fold) but statistically significant difference. CAT activity assays demonstrated that liver tissue has approximately three times more CAT activity than lymphocytes. Therefore, Comet assays were performed on primary Cat+/+, Cat+/-, and Cat-/- hepatocytes to determine if the Cat-/- cells were more susceptible to MMAIII than lymphocytes. The results showed that the Cat-/- hepatocytes exhibit higher levels of DNA strand breakage than the Cat+/+ (approximately fivefold) and Cat+/- (approximately twofold) hepatocytes exposed to MMAIII. Electron spin resonance using 5,5-dimethyl-1-pyrroline-N-oxide as the spin-trap agent detected the generation of center dot OH via MMAIII when H2O2 was present. These experiments suggest that CAT is involved in protecting cells against the genotoxic effects of the center dot OH generated by MMAIII. Environ. Mol. Mutagen. 54:317-326, 2013. (c) 2013 Wiley Periodicals, Inc.