Induction of genotoxic damage is not correlated with the ability to methylate arsenite in vitro in the leukocytes of four mammalian species.
Arsenic is a natural drinking water contaminant that impacts the health of large populations of people throughout the world; however, the mode or mechanism by which arsenic induces cancer is unclear. In a series of in vitro studies, we exposed leukocytes from humans, mice, rats, and guinea pigs to a range of sodium arsenite concentrations to determine whether the lymphocytes from these species showed differential sensitivity to the induction of micronuclei (MN) assessed in cytochalasin B-induced binucleate cells. We also determined the capacity of the leukocytes to methylate arsenic by measuring the production of MMA [monomethylarsinic acid (MMA(V)) and monomethylarsonous acid (MMA(III))] and DMA [dimethylarsinic acid (DMA(V)) and dimethylarsonous acid (DMA(III))]. The results indicate that cells treated for 2 hr at the G(0) stage of the cell cycle with sodium arsenite showed only very small to negligible increases in MN after mitogenic stimulation. Treatment of actively cycling cells produced induction of MN with increasing arsenite concentration, with the human, rat, and mouse lymphocytes being much more sensitive to MN induction than those of the guinea pig. These data gave an excellent fit to a linear model. The leukocytes of all four species, including the guinea pig (a species previously thought not to methylate arsenic), were able to methylate arsenic, but there was no clear correlation between the ability to methylate arsenic and the induction of MN.
Environmental Carcinogenesis Division MD-68, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
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Peng
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Sharma
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Kligerman
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007962:Leukocytes / Q000187:drug effects*; D008745:Methylation; D051379:Mice; D051381:Rats; D012044:Regression Analysis; D016192:Resting Phase, Cell Cycle; D017670:Sodium Compounds / Q000633:toxicity*
D018053:Arsenites; D017670:Sodium Compounds; D003571:Cytochalasin B; C017947:sodium arsenite