Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptopic cell death in dopaminergic cells.
We examined the acute toxicity of dieldrin, a possible environmental risk factor of Parkinson's disease, in a dopaminergic cell model, PC12 cells, to determine early cellular events underlying the pesticide-induced degenerative processes. EC(50) for 1 h dieldrin exposure was 143 microM for PC12 cells, whereas EC(50) for non-dopaminergic cells was 292-351 microM, indicating that dieldrin is more toxic to dopaminergic cells. Dieldrin also induced rapid, dose-dependent releases of dopamine and its metabolite, DOPAC, resulting in depletion of intracellular dopamine. Additionally, dieldrin exposure caused depolarization of mitochondrial membrane potential in a dose-dependent manner. Flow cytometric analysis showed generation of reactive oxygen species (ROS) within 5 min of dieldrin treatment, and significant increases in lipid peroxidation were also detected following 1 h exposure. ROS generation was remarkably inhibited in the presence of SOD. Dieldrin-induced apoptosis was significantly attenuated by both SOD and MnTBAP (SOD mimetic), suggesting that dieldrin-induced superoxide radicals serve as important signals in initiation of apoptosis. Furthermore, pretreatment with deprenyl (MAO-inhibitor) or alpha-methyl-L-p-tyrosine (TH-inhibitor) also suppressed dieldrin-induced ROS generation and DNA fragmentation. Taken together, these results suggest that rapid release of dopamine and generation of ROS are early cellular events that may account for dieldrin-induced apoptotic cell death in dopaminergic cells.
Kitazawa
M
M
Parkinson Disorders Research Program, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011-1250, USA.
Anantharam
V
V
Kanthasamy
A G
AG
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004026:Dieldrin / Q000008:administration & dosage / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000032:analysis / Q000378:metabolism; D015227:Lipid Peroxidation; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D016716:PC12 Cells; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D015102:3,4-Dihydroxyphenylacetic Acid; D007770:L-Lactate Dehydrogenase; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; D004026:Dieldrin; D004298:Dopamine