PCB neurotoxicity: Oxidative stress as a mechanism for neurodegeneration and compromised behavioral function

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. Polychlorinated biphenyls (PCBs) are persistent and widespread pollutants that have been associated with disruption of dopaminergic (DAergic) pathways, leading to neurological and cognitive impairments. However, the role ROS play in neurotoxicity in adults following PCB exposure remains unclear. Dopamine neurons, which degenerate during PD, are particularly sensitive to OS. Therefore, it was hypothesized that PCB exposure compromises DAergic neuron function by stimulating ROS production.; In vitro studies determined that PCB treatment produced elevated ROS levels, which preceded cell death, in DAergic cells. These observations were accompanied by DA depletion and an antioxidant defense response. The most notable finding was the robust elevation in heme oxygenase-1 (HO-1) levels in DAergic cells following PCB treatment. Additional studies tested the hypothesis that both HO-1 and Fe contribute to PCB neurotoxicity. PCB treatment was associated with intracellular Fe accumulation in DAergic cells. Anti-sense inhibition of HO-1 and Fe chelation protected against PCB-induced ROS production and cell death. Conversely, HO-1 overexpression in DAergic was associated with enhanced ROS production and vulnerability to cell death following PCB treatment. These data suggest HO-1 induction and Fe accumulation contribute to oxidative stress, DAergic cell injury, and death.; In vivo studies revealed that regional PCB accumulation in brain was accompanied by corresponding changes in behavioral function. Subchronic PCB exposure produced elevated locomotor activity with concurrent increases in OS-related proteins and tissue Fe levels in both DAergic and non-DAergic brain regions. These changes were paralleled by an elevation in oxidatively modified lipids and proteins. Furthermore, stereological analysis demonstrated the loss of midbrain DA and non-DA neurons following PCB exposure. These studies indicate that PCBs elicited widespread OS response, which could mediate neurodegeneration and behavioral abnormalities associated with exposure. Furthermore, these studies may contribute to the development of strategies for early detection and treatments that can be used to slow down or halt the progression of neurodegenerative processes.