Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat.
Environmental toxicants and, in particular, pesticides have been implicated as risk factors in Parkinson's disease (PD). The purpose of this study was to determine if selective nigrostriatal degeneration could be reproduced by systemic exposure of mice to the widely used herbicide paraquat. Repeated intraperitoneal paraquat injections killed dopaminergic neurons in the substantia nigra (SN) pars compacta, as assessed by stereological counting of tyrosine hydroxylase (TH)-immunoreactive and Nissl-stained neurons. This cell loss was dose- and age-dependent. Several lines of evidence indicated selective vulnerability of dopaminergic neurons to paraquat. The number of GABAergic cells was not decreased in the SN pars reticulata, and counting of Nissl-stained neurons in the hippocampus did not reveal any change in paraquat-treated mice. Degenerating cell bodies were observed by silver staining, but only in the SN pars compacta, and glial response was present in the ventral mesencephalon but not in the frontal cortex and cerebellum. No significant depletion of striatal dopamine followed paraquat administration. On the other hand, enhanced dopamine synthesis was suggested by an increase in TH activity. These findings unequivocally show that selective dopaminergic degeneration, one of the pathological hallmarks of PD, is also a characteristic of paraquat neurotoxicity. The apparent discrepancy between pathological (i.e., neurodegeneration) and neurochemical (i.e., lack of significant dopamine loss) effects represents another important feature of this paraquat model and is probably a reflection of compensatory mechanisms by which neurons that survive damage are capable of restoring neurotransmitter tissue levels.
The Parkinson's Institute, Sunnyvale, California 94089, USA.
Alison L
AL
McCormack
Mona
M
Thiruchelvam
Amy B
AB
Manning-Bog
Christine
C
Thiffault
J William
JW
Langston
Deborah A
DA
Cory-Slechta
Donato A
DA
Di Monte
D015655:1-Methyl-4-phenylpyridinium / Q000737:chemistry; D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D015415:Biomarkers; D004298:Dopamine / Q000378:metabolism*; D004781:Environmental Exposure; D005911:Gliosis / Q000139:chemically induced; D006540:Herbicides / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D006719:Homovanillic Acid / Q000032:analysis; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010269:Paraquat / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D010300:Parkinson Disease / Q000453:epidemiology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D020734:Parkinsonian Disorders / Q000473:pathology; D012307:Risk Factors; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D015415:Biomarkers; D006540:Herbicides; D009419:Nerve Tissue Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D010269:Paraquat; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006719:Homovanillic Acid