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Tributyltin chloride (TBT), an endocrine-disrupting chemical, has been used as a heat stabilizer, agricultural pesticide, and component of antifouling paints. In this study, we investigated the concentration dependence of the mechanisms of tributyltin cytotoxicity in PC12 cells. Exposure of PC12 cells to both 500nM and 2μM tributyltin increased the number of cells showing nuclear fragmentation, a typical apoptotic feature, and activated caspase-3. The peak Ca²⁺ concentration in 2μM tributyltin–treated cells was higher than that in 500nM tributyltin–treated cells. The intracellular Ca²⁺ increase induced by 2μM tributyltin was mediated by Ca²⁺ release from both inositol 1,4,5-trisphosphate receptor and ryanodine receptor, while the Ca²⁺ increase induced by 500nM tributyltin was mediated through the voltage-dependent calcium channel (VDCC). Next, we investigated whether the mechanisms leading to cell death …