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Arsenic Is A Genotoxic Carcinogen
Citation:
Kligerman, A. Arsenic Is A Genotoxic Carcinogen. Env. Mutagenesis Geneomics Society Meeting, Monterey, CA, September 21 - 25, 2013.
Impact/Purpose:
This is a presentation summarizing our 13 years of work understanding how arsenic induces genetic damage. Will be presented at the Environmental Mutagenesis Society Meeting, September 21-25, 2013, Monterey, California
Description:
Arsenic is a recognized human carcinogen; however, there is controversy over whether or not it should be considered a genotoxic carcinogen. Many possible modes of action have been proposed on how arsenic induces cancer, including inhibiting DNA repair, altering methylation patterns, changing cell signaling, inducing DNA damage, and the current in-vogue hypothesis of causing cytotoxicity followed by proliferative regeneration. These mechanisms may not be and probably are not mutually exclusive. In this presentation evidence is provided that arsenic, specifically in the trivalent methylated form, is a potent genotoxic carcinogen that induces DNA damage, including chromosome breakage and numerical chromosome changes (aneuploidy), but it is not a point mutagen. In fact, dimethylarsinous acid (DMAIII) is over 400 times more potent a clastogen as sodium arsenite (NaAsIII). In addition, the data indicate that arsenic acts through reactive oxygen species (ROS) to induce DNA damage and hence chromosome breakage. Cells from catalase knock-out mice were approximately 10 times more sensitive to monomethylarsonous acid (MMAIII) then were cells from wild-type mice. Experiments with antioxidants and N-acetylcysteine suggest that the numerical chromosomal changes are caused by the attack of arsenic on sulfhydryl groups in the spindle. Proliferative regeneration, by itself, does not seem to be a sufficient mechanism to account for the potency of arsenic as a carcinogen. Finally, an experiment will be proposed that might shed additional light on arsenic’s mode of action. (This abstract does not necessarily reflect the views of the US EPA).