title: Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems.
abstract: Recent epidemiologic studies have demonstrated a link between organochlorine and pesticide exposure to an enhanced risk for neurodegenerative disorders such as Parkinson's disease (PD). A common biological phenomenon underlying cell injury associated with both polychlorinated biphenyl (PCB) exposure and dopaminergic neurodegeneration during aging is oxidative stress (OS). In this study, we tested the hypothesis that oral PCB exposure, via food ingestion, impairs dopamine systems in the adult murine brain. We determined whether PCB exposure was associated with OS in dopaminergic neurons, a population of cells that selectively degenerate in PD. After 4 weeks of oral exposure to the PCB mixture Aroclor 1254, several congeners, mostly ortho substituted, accumulated throughout the brain. Significant increases in locomotor activity were observed within 2 weeks, which persisted after cessation of PCB exposure. Stereologic analyses revealed a significant loss of dopaminergic neurons within the substantia nigra and ventral tegmental area. However, striatal dopamine levels were elevated, suggesting that compensatory mechanisms exist to maintain dopamine homeostasis, which could contribute to the observed increases in locomotor activity following PCB exposure. Biochemical experiments revealed alterations in OS markers, including increases in SOD and HO-1 levels and the presence of oxidatively modified lipids and proteins. These findings were accompanied by elevated iron levels within the striatal and midbrain regions, perhaps due to the observed dysregulation of transferrin receptors and ferritin levels following PCB exposure. In this study, we suggest that both OS and the uncoupling of iron regulation contribute to dopamine neuron degeneration and hyperactivity following PCB exposure.
authors.affiliation: Department of Environmental Medicine, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, USA.
authors.forename: Donna W
authors.initials: DW
authors.lastname: Lee
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Notter
authors.forename: Mona
authors.initials: M
authors.lastname: Thiruchelvam
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Dever
authors.forename: Richard
authors.initials: R
authors.lastname: Fitzpatrick
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kostyniak
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Cory-Slechta
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Opanashuk
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D020111:Chlorodiphenyl (54% Chlorine) / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004785:Environmental Pollutants; D008565:Membrane Proteins; D020111:Chlorodiphenyl (54% Chlorine); D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; D004298:Dopamine
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