Polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress plays a role in dopaminergic cell injury.
Oxidative stress (OS) is thought to participate in the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Excessive reactive oxygen species (ROS) production can occur during the normal aging process or following exposure to environmental toxicants. Dopamine neurons, which degenerate during PD, are particularly sensitive to oxidative stress. Polychlorinated biphenyls (PCBs), persistent and widespread pollutants, have been shown to adversely impact dopaminergic (DAergic) pathways, but the role ROS play in neurotoxicity remains unclear. To test the hypothesis that PCB exposure compromises dopamine neurons by stimulating ROS production, the direct toxicity and oxidative stress response following PCB exposure was examined both in MN9D dopamine cells and primary mesencephalic cultures. PCBs induced a time- and concentration-dependent increase in ROS production, which preceded cytotoxicity. Whereas intracellular GSH depletion exacerbated PCB effects, antioxidant pretreatment attenuated ROS production and cell death. Coincident alterations in antioxidant defense enzymes also accompanied ROS production, including decreased MnSOD and increased CuZnSOD protein levels. The robust elevation in heme oxygenase-1 levels further support the activation of oxidative stress mechanisms following PCB exposure. Furthermore, PCBs produced concentration-dependent reductions in intracellular dopamine levels and elevated dopamine turnover. Although the intracellular source of ROS remains unknown, these results suggest that sublethal PCB concentrations activate an oxidative stress-related pathway, which potentially disrupts dopamine neuron function.
Department of Environmental Medicine, Box EHSC, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
D W
DW
Lee
L A
LA
Opanashuk
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D020111:Chlorodiphenyl (54% Chlorine); D004298:Dopamine