Document Detail

Modulation of antioxidant defense systems by the environmental pesticide maneb in dopaminergic cells.
MedLine Citation:
PMID:  15527874     Owner:  NLM     Status:  MEDLINE    
A lack of evidence supporting a role of heritability in the development of idiopathic Parkinson's disease (PD) has implicated exposures to environmental contaminants in the disease etiology. Epidemiological and clinical studies, as well as animal models of the PD phenotype, have consistently linked agrichemical exposure with dopaminergic (DAergic) damage, particularly through oxidative stress mechanisms. Maneb (MB) is a dithiocarbamate (DTC) fungicide that has specifically been implicated to have adverse effects on dopamine (DA) systems, but the role MB plays in modulating the oxidative state of DAergic cells has not previously been described. Since glutathione (GSH) is a major cellular antioxidant, it was hypothesized that exposure to MB would disrupt this system. The current study primarily utilized the PC12 cell line, which displays a catecholaminergic phenotype. Low concentrations of MB (50-1000 ng/ml) had little effect on cell viability, as measured by LDH release. These same concentrations, however, led to increases in GSH and its oxidized form, GSSG. Effects on viability and GSH were correlated to a primary mesencephalic culture system. Furthermore, these effects were markedly different from those observed with the classical oxidative stressor and pesticide, paraquat (PQ). To determine how MB would affect cells in which antioxidant systems were compromised, PC12 cells were treated with L-buthionine-(S,R)-sulfoximine (BSO) to deplete cellular GSH, followed by treatment with MB. Results suggest that following an insult to the GSH antioxidant system, MB can act as an additional insult to the system and prevent the normal recovery of those defenses. Altered protein levels of heme oxygenase-1 (HO-1) further indicated an oxidative stress response elicited by MB in PC12 cells. DAergic neurons, as a population, are inherently vulnerable to oxidative stress, and the disruption of antioxidant systems by the fungicide MB may contribute to the neurodegeneration of these cells, especially with concurrent exposures to other environmentally relevant oxidative stressors, such as PQ.
Brian K Barlow; Donna W Lee; Deborah A Cory-Slechta; Lisa A Opanashuk
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neurotoxicology     Volume:  26     ISSN:  0161-813X     ISO Abbreviation:  Neurotoxicology     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-11-05     Completed Date:  2005-01-11     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7905589     Medline TA:  Neurotoxicology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  63-75     Citation Subset:  IM    
Department of Environmental Medicine, School of Medicine, University of Rochester, Rochester, NY, USA.
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MeSH Terms
Actins / metabolism
Antioxidants / metabolism*
Cell Line, Tumor
Cell Survival / drug effects
Cells, Cultured
Dopamine / physiology*
Fungicides, Industrial / toxicity*
Glutamate-Cysteine Ligase / metabolism
Glutathione / metabolism
Glutathione Peroxidase / metabolism
Heme Oxygenase (Decyclizing) / metabolism
Heme Oxygenase-1
L-Lactate Dehydrogenase / metabolism
Maneb / toxicity*
Mesencephalon / cytology,  metabolism
Neurons / drug effects,  metabolism
Oxidative Stress / drug effects
Grant Support
Reg. No./Substance:
0/Actins; 0/Antioxidants; 0/Fungicides, Industrial; 12427-38-2/Maneb; 70-18-8/Glutathione; EC Dehydrogenase; EC Peroxidase; EC Oxygenase (Decyclizing); EC Oxygenase-1; EC Ligase

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