Induction of apoptosis in human lymphocytes by the herbicide 2,4-dichlorophenoxyacetic acid

Dimethylammonium salt of 2,4-dichlorophenoxyacetic acid (DMA-2,4-D) is a wi dely used herbicide that is considered moderately toxic. In the present stu dy we found that DMA-2,4-D is able to cause apoptosis in peripheral blood l ymphocytes of healthy individuals and Jurkat T cells. Apoptosis induced by DMA-2,4-D was dose and time dependent, independent of Fas, TNF receptor 1 o r the aromatic hydrocarbon receptor, and involved disruption of the mitocho ndrial transmembrane potential and activation of caspase-9. ZVAD-FMK, a bro ad-spectrum inhibitor of caspases, blocked DMA-2,4-D-induced apoptosis comp letely. While an inhibitor of caspase-9, as well as caspase-9 and caspase-3 inhibitors in combination, strongly blocked DMA-2,4-D-induced apoptosis, a n inhibitor of caspase-3 had a moderate inhibitory effect. Unlike Fas-media ted apoptosis, the initiator caspase, caspase-8, was not involved in DMA-2, 4-D-induced apoptosis. Transfection of Jurkat cells with Bcl-2 prevented DM A-2,4-D-induced disruption of the mitochondrial transmembrane potential and led to a complete blockade of apoptosis. Our data indicate that DMA-2,4-D kills human lymphocytes by initiating apoptosis via a direct effect on mito chondria. The activation of caspases occurs downstream of mitochondrial dam age, and the dysfunction of mitochondria appears to be sufficient for trigg ering all downstream events leading to apoptosis. Human Immunology 62, 64-7 4 (2001). (C) American Society for Histocompatibility and Immunogenetics, 2 001. Published by Elsevier Science Inc.