Uptake of inorganic and organic derivatives of arsenic associated with induced cytotoxic and genotoxic effects in Chinese hamster ovary (CHO) cells.
Humans are exposed to arsenic and their org. derivs., which are widely distributed in the environment, via food, water, and to a lesser extent, via air. Following uptake, inorg. arsenic undergoes biotransformation to mono- and dimethylated metabolites. Recent findings suggest that the methylation reactions represent a toxification rather than a detoxification pathway. In the present study, the genotoxic effects and the cellular uptake of inorg. arsenic [arsenate, Asi(V); arsenite, Asi(III)] and the methylated arsenic species monomethylarsonic acid [MMA(V)], monomethylarsonous acid [MMA(III)], dimethylarsinic acid [DMA(V)], dimethylarsinous acid [DMA(III)], trimethylarsenic oxide [TMAO(V)] were investigated in Chinese hamster ovary (CHO-9) cells. The chems. were applied at different concns. (0.1 mM to 10 mM) for 30 min and 1 h, resp. Cytotoxic effects were investigated by the trypan blue extrusion test and genotoxic effects by the assessment of micronucleus (MN) induction, chromosome aberrations (CA), and sister chromatid exchanges (SCE). Intracellular arsenic concns. were detd. by ICP-MS techniques. The results show that MMA(III) and DMA(III) induce cytotoxic and genotoxic effects to a greater extent than MMA(V) or DMA(V). Viability was significantly decreased after incubation (1 h) of the cells with >= 1 mM Asi(III), >= 1 mM Asi(V), >= 500 mM MMA(III), >= 100 mM MMA(V), and 500 mM DMA(V) and >= 0.1 mM DMA(III). TMAO(V) was not cytotoxic at concns. up to 10 mM. A significant increase of the no. of MN, CA and SCE was found for DMA(III) and MMA(III). Asi(III + V) induced CA and SCE but no MN. TMAO(V), MMA(V) and DMA(V) were not genotoxic in the concn. range tested (up to 5 mM). The nuclear division index (NDI) was not affected by any of the tested arsenic compds. after a recovery period of 14 to 35 h. When the uptake of the chems. was measured by ICP-MS anal., it was found that only 0.03% MMA(V) and DMA(V), and 2% MMA(III), Asi(III) and (V) were taken up by the cells. In comparison, 10% of the DMA(III) dose was taken up. The total intracellular concn. of all arsenic compds. increased with increasing arsenic concns. in the culture medium. Taken together, these data demonstrate that arsenic compds. in the trivalent oxidn. state exhibit the strongest genotoxic effects. Trivalent organoarsenic compds. are more membrane permeable than the pentavalent species. The potency of the DNA damage decreases in the order DMA(III) > MMA(III) > Asi(III and V) > MMA(V) > DMA(V) > TMAO(V). The authors postulate that the induction of genotoxic effects caused by the methylated arsenic species is primarily dependent upon their ability to penetrate cell membranes.
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