Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease?
The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. C57BL/6 mice were exposed to either paraquat (5-10 mg/kg) or maneb (15-30 mg/kg) i.p. alone or in combination once a week for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with activity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediately post-injection only by combined exposures, and returned to control levels or below within 48 h. Reductions in tyrosine hydroxylase immunoreactivity, measured 3 days after the last injection, resulted only from combined exposure and were detected in dorsal striatum, but not in the nucleus accumbens. The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents.
Departments of Environmental Medicine, Pathology and Laboratory Medicine, Laboratory Animal Medicine and the NIEHS Environmental Health Sciences Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
M
M
Thiruchelvam
B J
BJ
Brockel
E K
EK
Richfield
R B
RB
Baggs
D A
DA
Cory-Slechta
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004781:Environmental Exposure / Q000009:adverse effects*; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D017072:Neostriatum / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D010269:Paraquat / Q000633:toxicity*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D012307:Risk Factors; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D008344:Maneb; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D004298:Dopamine