Cytotoxic and genotoxic effects of As, MMA, and DMA on leukocytes and stimulated human lymphocytes.

Abstract

Inorganic arsenic is a human carcinogen associated with different types of cancer. Arsenic metabolism produces two methylated species: monomethylarsonic and dimethylarsinic acids. Although this metabolic route has been involved in arsenic detoxification, it is still not clear whether these methylated metabolites participate in the carcinogenic process. In this work, we studied the cytotoxic and genotoxic effects of arsenic and its metabolites. Cytotoxicity was evaluated in cultured lymphocytes from three donors. Mitotic and replication indices were the parameters analyzed. The results indicate a clear cytotoxic effect by sodium arsenite but not by its metabolites. Genotoxicity was assessed by the single cell gel electrophoresis assay. Sodium arsenite increased DNA migration in stimulated lymphocytes only at doses greater than 5 x 10(-6) M; meanwhile in leukocytes a weak response was observed. Monomethylarsonic acid produced in leukocytes a weak induction of DNA damage, while in stimulated lymphocytes, a dose-increase in DNA migration was observed. The injury caused by dimethylarsinic acid was more evident than that observed in cultures treated with sodium arsenite and monomethylarsonic acid in stimulated lymphocytes, although in leukocytes no effect on DNA migration was found. In conclusion, only sodium arsenite had the capacity to alter mitotic and replication indices, while sodium arsenite and its metabolites were capable of inducing single strand DNA breaks on stimulated human lymphocytes treated in vitro for 24 h; however, the differences observed were between individual responses, one donor being more susceptible even at the lower doses. This individual susceptibility to arsenic compounds has been repeatedly observed for different end-points and should be studied further.