Abstract

Treatment of rat thymocytes with micromolar concentrations of tributyltin caused a rapid increase in the cytosolic free Ca 2+ concentration that was inhibited by Ni 2+, which blocks Ca 2+ influx through membrane channels. The elevation of cytosolic Ca 2+ was associated with extensive DNA fragmentation, which was prevented by pretreatment of the cells with either of the intracellular Ca 2+ 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 Ca 2+ chelators or by removing extracellular Ca 2+ with ethylene glycol bis(β-aminoethyl ether) N,N′-tetraacetic acid. The pattern of DNA fragmentation was characteristic of that produced by agents which activate a Ca 2+- and Mg 2+-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 Ca 2+, 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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