Induction of Aneuploidy, Centrosome Abnormality, Multipolar Spindle, and Multipolar Division in Cultured Mammalian Cells Exposed to an Arsenic Metabolite, Dimethylarsinate.

Abstract

Toxicological studies of arsenic compounds were conducted in cultured mammalian cells to investigate the effects of glutathione (GSH) depletion. Dimethylarsinate DMA(V) was not cytotoxic in cells depleted of GSH, but was found to be cytotoxic when GSH was present outside the cells. The results suggested that a reactive form of DMA(V) was generated through interaction with GSH. Dimethylarsine iodide DMI(III) was used as a model compound of DMA(III), and the biological effects were investigated. DMI(III) was about 10000 times more toxic to the cells than DMA(V). Chromosome structural aberrations and numerical changes, such as aneuploidy, were induced by DMI(III). DMA(V) induced multiple foci of the centrosome protein, γ-tubulin, which were colocalized with multipolar spindles in mitotic cells. The multiple foci coalesced into a single dot on disruption of the microtubules (MT). However, reorganization of the MT caused multiple foci of γ-tubulin, suggesting that the induction of centrosome abnormalities by DMA(V) required intact MT. Inhibition of the MT-dependent motor, kinesin, prevented formation of multiple foci of γ-tubulin, which pointed to the involvement of the MT-dependent mitotic motor, kinesin, in the maintenance of centrosome abnormalities. DMI(III) caused abnormal cytokinesis (multipolar division). In addition, DMI(III) caused morphological transformation in Syrian hamster embryo cells. Consideration of the overall process following the centrosome abnormalities caused by DMA(V) suggested a mode of cytotoxicity in which the mitotic centrosome is a critical target.