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ToxSci Advance Access originally published online on November 30, 2005
Toxicological Sciences 2006 90(1):159-167; doi:10.1093/toxsci/kfj052
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Heme-Oxygenase-1 Promotes Polychlorinated Biphenyl Mixture Aroclor 1254-Induced Oxidative Stress and Dopaminergic Cell Injury

Donna W. Lee, Robert M. Gelein and Lisa A. Opanashuk1

Department of Environmental Medicine, University of Rochester of School of Medicine and Dentistry, Rochester, New York 14642

Received September 14, 2005; accepted November 16, 2005

Dopaminergic (DAergic) systems have been identified as putative targets for polycholorinated biphenyl (PCB) actions. However, the precise mechanisms leading to neurotoxicity are unresolved. Reactive oxygen species (ROS) were recently shown to mediate injury in DAergic MN9D cells following exposure to Aroclor 1254 (A1254), a commercial PCB mixture. The oxidative stress response in DAergic cells included a persistent expression of heme oxygenase-1 (HO-1). This study tested the hypothesis that a sustained PCB-induced HO-1 response leads to abnormally high Fe levels, which generates ROS production and mediates death in the MN9D DAergic cell model. Accordingly, results indicated that A1254 augmented intracellular Fe levels in MN9D cells after 24 h. Fe chelation by desferoxamine or pharmacologic inhibition of HO activity with tin-protoporphyrin reduced Fe accumulation, ROS production, and cytotoxicity following A1254 exposure. HO-1 over-expression predisposed MN9D DAergic cells to enhanced ROS production and cell death in response to PCBs. Conversely, antisense inhibition of HO-1 expression prevented PCB-induced ROS production and cell death. These observations suggest that enhanced HO-1 catalytic activity and subsequent liberation of Fe participate in neurotoxic DAergic cell injury caused by A1254 exposure in vitro.

Key Words: PCB; neurotoxicity; reactive oxygen species (ROS); iron; neurodegeneration.


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