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A genetic approach to elucidate the genotoxic pathway of monomethylarsonous acid suggests a key role for catalase
Citation:
Munz, G., K. Wallace, AND A. D. KLIGERMAN. A genetic approach to elucidate the genotoxic pathway of monomethylarsonous acid suggests a key role for catalase. Presented at Environmental Mutagen Society 42nd Annual Meeting, Montreal, QC, CANADA, October 15 - 19, 2011.
Impact/Purpose:
Our studies are centered on identifying a reactive oxygen species involved in the genotoxicity of arsenic using a catalase (Cat) knock-out mouse model, which is impaired in its ability to break down hydrogen peroxide (H202) that leads to an increase in hydroxyl radicals (-OH)
Description:
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. Our studies are centered on identifying a reactive oxygen species involved in the genotoxicity of arsenic using a catalase (Cat) knock-out mouse model, which is impaired in its ability to break down hydrogen peroxide (H202) that leads to an increase in hydroxyl radicals (•OH). We assessed the induction of DNA damage using the comet assay following exposure of Cat+/+ and Cat–/– primary lymphocytes to monomethylarsonous acid (MMAIII) to identify the potential role of H202 in mediating cellular effects of this metalloid. Our results showed that the Cat–/– lymphocytes are more susceptible to MMAIII than the Cat+/+ lymphocytes by a small (1.49-fold), but statistically significant difference. Cat activity assays demonstrated that liver tissue has ~3 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. Preliminary results have shown that the Cat–/–hepatocytes exhibit higher levels of DNA strand breakage than the Cat+/+ and Cat+/– hepatocytes exposed to MMAIII. Our experiments suggest that Cat is involved in protecting cells against MMAIII-generated H202, and that the •OH might be involved in its genotoxic pathway. Furthermore, individuals who harbor genetic polymorphisms in their Cat gene could exhibit altered susceptibility to arsenic toxicity. [This is an abstract or proposed presentation and does not necessarily reflect EPA policy.]