Tributyltin stimulates apoptosis in rat thymocytes.
Treatment of rat thymocytes with micromolar concentrations of tributyltin caused a rapid increase in the cytosolic free Ca2+ concentration that was inhibited by Ni2+, which blocks Ca2+ influx through membrane channels. The elevation of cytosolic Ca2+ was associated with extensive DNA fragmentation, which was prevented by pretreatment of the cells with either of the intracellular Ca2+ chelators quin-2 or 1,2-bis(2-amino-phenoxy)ethane-N',N',N',N',-tetraacetic acid. Loss of thymocyte viability, which followed DNA fragmentation, was also prevented by the two Ca2+ chelators or by removing extracellular Ca2+ with ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid. The pattern of DNA fragmentation was characteristic of that produced by agents which activate a Ca2(+)- and Mg2(+)-dependent endogenous endonuclease during apoptosis or programmed cell death. Additional studies showed that other organotin compounds, including trimethyltin, triphenyltin, and dibutyltin had minimal effects on cytosolic Ca2+, DNA fragmentation, and cell viability. These results are consistent with a greater susceptibility of thymocytes to tributyltin and provide a basis for understanding its selective immunotoxicity in vivo.
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Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
Nicotera
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Manzo
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Orrenius
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D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000494:pharmacology*
D014220:Trialkyltin Compounds; C011559:tributyltin; D004247:DNA; D002118:Calcium