Induction of structural and numerical changes of chromosome, centrosome abnormality, multipolar spindles and multipolar division in cultured Chinese hamster V79 cells by exposure to a trivalent dimethylarsenic compound.
Dimethylarsine iodide (DMI) was used as a model compound of trivalent dimethylarsenicals [DMA(III)], and the biological effects were extensively investigated in cultured Chinese hamster V79 cells. When the cytotoxic effects of DMA(III) were compared with those of inorganic arsenite and dimethylarsinic acid [DMA(V)], DMA(III) was about 10,000 times more potent than DMA(V), and it was even 10 times more toxic than arsenite. Depletion of cell glutathione (GSH) did not influence the cytotoxic effects of DMA(III), whereas it enhanced the cytotoxicity of arsenite. Chromosome structural aberrations, such as gaps, breaks and pulverizations, and numerical changes, such as aneuploidy, hyper- and hypo-tetraploidy, were induced by DMA(III) in a concentration-dependent manner. Mitotic index increased 9-12h after the addition of DMA(III), and then declined. By contrast, the incidence of multinucleated cells increased conversely with the decrease in mitotic index at and after 24h of exposure. The mitotic cell-specific abnormality of centrosome integrity and multipolar spindles were induced by DMA(III) in a time- and concentration-dependent manner. Moreover, DMA(III) caused abnormal cytokinesis (multipolar division) at concentrations that were effective in causing centrosome abnormality, multipolar spindles and aneuploidy. These results showed that DMA(III) was genotoxic on cultured mammalian cells. Results also suggest that DMA(III)-induced multipolar spindles and multipolar division may be associated with the induction of aneuploidy. In addition, the centrosome may be a primary target for cell death via multinucleated cells.
Ochi
Takafumi
T
Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan. tkfmochi@pharm.teikyo-u.ac.jp
Suzuki
Tosihide
T
Isono
Hideo
H
Schlagenhaufen
Claudia
C
Goessler
Walter
W
Tsutsui
Takeki
T
D000782:Aneuploidy; D000818:Animals; D018053:Arsenites / Q000633:toxicity; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018385:Centrosome / Q000187:drug effects*; D002869:Chromosome Aberrations / Q000139:chemically induced*; D006224:Cricetinae; D003412:Cricetulus; D005978:Glutathione / Q000494:pharmacology; D009152:Mutagenicity Tests; D008941:Spindle Apparatus / Q000187:drug effects*
D018053:Arsenites; D002101:Cacodylic Acid; D005978:Glutathione; C015001:arsenite