Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptotic cell death in dopaminergic cells

We examined the acute toxicity of dieldrin, a possible environmental risk f actor of Parkinson's disease, in a dopaminergic cell model, PC12 cells, to determine early cellular events underlying the pesticide-induced degenerati ve processes. EC50 for 1 h dieldrin exposure was 143 muM for PC12 cells, wh ereas EC50 for non-dopaminergic cells was 292-351 muM, indicating that diel drin is more toxic to dopaminergic cells. Dieldrin also induced rapid, dose -dependent releases of dopamine and its metabolite, DOPAC, resulting in dep letion of intracellular dopamine. Additionally, dieldrin exposure caused de polarization of mitochondrial membrane potential in a dose-dependent manner . Flow cytometric analysis showed generation of reactive oxygen species (RO S) within 5 min of dieldrin treatment, and significant increases in lipid p eroxidation were also detected following 1 h exposure. ROS generation was r emarkably inhibited in the presence of SOD. Dieldrin-induced apoptosis was significantly attenuated by both SOD and MnTBAP (SOD mimetic), suggesting t hat dieldrin-induced superoxide radicals serve as important signals in init iation of apoptosis. Furthermore, pretreatment with deprenyl (MAO-inhibitor ) or alpha -methyl-L-p-tyro sine (TH-inhibitor) also suppressed dieldrin-in duced ROS generation and DNA fragmentation. Taken together, these results s uggest that rapid release of dopamine and generation of ROS are early cellu lar events that may account for dieldrin-induced apoptotic cell death in do paminergic cells. (C) 2001 Elsevier Science Inc.