Organotin-induced caspase activation and apoptosis in human peripheral blood lymphocytes

In the present study, we show that the immunotoxicant, tributyltin (TBT), i nduces a dose-dependent activation of caspases followed by typical apoptoti c morphology in resting human peripheral blood lymphocytes, TBT also caused an early loss of mitochondrial membrane potential (Delta (psim)) and relea se of cytochrome c, suggesting that apoptosis was triggered by the mitochon drial pathway. When CD4+ T-cells were sorted from peripheral blood and expo sed to TBT for 30 min, caspase activation and apoptosis were induced. Inter estingly, in the sorted CD8+ T-cell population, caspase activation was not observed until 2 h of TBT exposure, suggesting that these cells were more r esistant toward TBT. Moreover, a time-dependent induction of caspase activi ty was also detected in CD3-stimulated peripheral blood lymphocytes. This c aspase activation was not associated with cytochrome c release or loss of m itochondrial Delta (psi) and did not lead to apoptotic morphology, although it did lead to both PARP and DFF cleavage. We also noticed a concomitant i nduction of Hsp27, and it awaits to be seen if this chaperone may interfere with the processing of nuclear protein substrates downstream from these pr imary caspase-3 substrates. Moreover, no increase in caspase activation or induction of apoptosis was observed after TBT treatment in these cells. Ins tead, the cells were directed toward necrotic deletion. Taken together, the se data suggest that TBT-induced deletion of peripheral lymphocytes is like ly to be a component in the overall risk for immunotoxic responses in expos ed humans.