Developmental exposure to the pesticides paraquat and maneb and the Parkinson's disease phenotype.
Idiopathic Parkinson's disease (PD) is associated with advanced age, but it is still unclear whether dopaminergic neuronal death results from events initiated during development, adulthood, or represents a cumulative effect across the span of life. This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. C57BL/6 mice were treated daily with saline, 0.3 mg/kg PQ, 1 mg/kg MB or PQ + MB from post-natal (PN) days 5 to 19. At 6 weeks, a 20% decrease in activity was evident only in the PQ + MB group, with a further decline (40%) observed at 6 months. A subset of mice were re-challenged as adults with saline, 10 mg/kg PQ, 30 mg/kg MB, or PQ + MB 2 x a week for 3 weeks. Mice exposed developmentally to PQ + MB and rechallenged as adults were the most affected, showing a 70% reduction in motor activity 2 weeks following the last rechallenge dose. Striatal DA levels were reduced by 37% following developmental exposure to PQ + MB only, butfollowing adult re-challenge levels were reduced by 62%. A similar pattern of nigral dopaminergic cell loss was observed, with the PQ + MB treated group exhibiting the greatest reduction, with this loss being amplified by adult re-challenge. Developmental exposure to PQ or MB alone produced minimal changes. However, following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together, these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.
Thiruchelvam
Mona
M
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Richfield
Eric K
EK
Goodman
Becky M
BM
Baggs
Raymond B
RB
Cory-Slechta
Deborah A
DA
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D005659:Fungicides, Industrial / Q000633:toxicity*; D006540:Herbicides / Q000633:toxicity*; D006719:Homovanillic Acid / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity*; D010300:Parkinson Disease / Q000473:pathology*; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D005659:Fungicides, Industrial; D006540:Herbicides; D008344:Maneb; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D004298:Dopamine; D006719:Homovanillic Acid