Elsevier

Brain Research

Volume 873, Issue 2, 11 August 2000, Pages 225-234
Brain Research

Research report
Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease?

https://doi.org/10.1016/S0006-8993(00)02496-3Get rights and content

Abstract

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.

Introduction

Parkinson’s disease (PD) is a chronic neurological disorder of likely multi-factorial origin characterized by resting tremor, rigidity and bradykinesia, with symptoms reflecting damage to the nigrostriatal dopamine system. Epidemiological studies have identified exposure to agricultural chemicals as potential environmental risk factors for PD [16], [17], [20], [29], [43], an assertion supported by a recent comprehensive study of over 19 000 white male twins indicating that idiopathic PD with onset after age 50 could not be explained by genetic heritability [51]. Variation in PD mortality by geographical regions, as reported in several countries, has also been interpreted as consistent with an environmental exposure etiology [22], [26], [49].

The herbicide paraquat (N,N′-dimethyl-4,4′-bipyridylium) has been repeatedly posed as a candidate environmental agricultural chemical risk factor owing to its structural similarity to MPP+ (1-methyl-4-phenylpyridinium ion), the active component of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a synthetic heroin compound demonstrated to produce a Parkinsonian-syndrome in humans following inadvertent exposure [25]. Although its entry is impeded, paraquat (PQ) does cross the blood–brain barrier, where higher levels are actually evident at 24 h post-administration than at 0.5 h [57]. Both MPP+ and Parkinson’s Disease preferentially target melanin-containing nerve cells, and paraquat likewise accumulates in neuromelanin [11], [18], [19], [27]. Attempts to relate paraquat exposure to PD, however, have produced equivocal results. While injections of PQ directly into brain can change dopamine levels and behavior and produce neuronal loss [2], [8], [28], [60], systemic PQ administration does not yield consistent evidence of neurotoxicity in rodents [2], [30], [39].

The restricted focus on paraquat as an environmental risk factor has obscured the fact that it is a member of only one class of agricultural chemicals known to impair dopamine function. Dithiocarbamate fungicides also possess potent dopaminergic activity. The diethyldithiocarbamates, one class of dithiocarbamates, potentiate the neurotoxicity of MPTP in vivo [33], [55]. Maneb (manganese ethylenebisdithiocarbamate) administered acutely i.p., exacerbates the reductions in locomotor activity and the increases in catalepsy produced by MPTP in mice, and, by itself, inhibits locomotor activity and increases haloperidol-induced catatonia [34], [50]. Neurological impairments resembling those of PD have been reported in agricultural workers exposed to maneb (MB) [14], [32]. Mancozeb (manganese-zinc-ethylenebisdithiocarbamate) and zineb (zinc-ethylenebisdithiocarbamate), two other members of this class, dose-dependently reduce high affinity dopamine uptake and numbers of tyrosine hydroxylase (TH) positive neurons and increase cytotoxicity in mesencephalic striatal primary co-cultures [46]. Similar effects have been described with the organochlorine pesticide dieldrin, an inhibitor of mitochondrial respiration, residual levels of which were found in brains of 30% of PD patients and not in control brains [15], [42]. Additionally, triadimefon, a triazole fungicide, blocks the dopamine transporter and produces behavioral effects resembling those of cocaine and d-amphetamine [10], [21], [38], [53], [54].

Of particular interest with respect to the etiologic basis of Parkinson’s disease is the marked geographical overlap in the estimated annual agricultural use of paraquat and maneb (Fig. 1) which includes the Northeast and Plains states, the mid-Atlantic and Southeast states, Texas and the Pacific Coast states. This extensive geographical overlap in use suggests overlap as well in exposures of human populations to these chemicals. It also formulates a basis for a multiple-hit environmental model for Parkinsonism in which exposure to an individual chemical may be insufficient to induce overt disease, whereas exposures occurring in conjunction and provoking changes in multiple components of dopamine system function may preclude homeostatic re-regulation such that neuropathological changes ensue. Interestingly, age-adjusted PD mortality rates, as recently reported by Lanska et al. [26], also exhibited the highest prevalence in the Northeastern states, mid-Atlantic, upper Midwestern states and the Pacific Coast states.

The current study examined the possibility that subclinical doses of these agricultural chemicals could engender detectable dopaminergic changes when administered in combination. It compared the effects of combined PQ+MB treatment to effects produced by each compound administered alone on locomotor activity, TH density, levels of dopamine and metabolites and dopamine turnover in C57Bl/6 mice.

Section snippets

Animals

Male C57BL/6 mice (6 weeks old) were purchased from Taconic Farms (New York). Animals were housed one to a cage with food and water available ad libitum in a room maintained under constant temperature and humidity conditions with a 12:12 light–dark cycle. All mice were habituated to the vivarium for at least 1 week prior to commencement of experiments. All animals were cared for and treated in accord with NIH and University of Rochester Animal Care and Use Committee guidelines.

Chemicals

All solvents for

Body weight and lung assessments

Body weights showed virtually no treatment-related effects over the course of the experiment, either when body weights collected prior to each motor activity session were compared over the entire experiment, when body weights from habituation session 3 were compared to:

(i) body weights on the last day of the experiment.

(ii) to body weights on the 4 injection days only. Lungs were graded for signs of alveolitis, bronchiolitis, bronchitis, lymphoid aggregation, bronchiectasis, and fibrosis and

Discussion

These findings demonstrate potentiated effects on nigrostriatal dopamine systems of combined exposures to members of two different agricultural chemical classes known to adversely impact dopamine systems. These chemicals sustain overlapping geographical use suggesting potential human exposures to both. Motor activity decrements were potentiated under conditions of combined exposures to PQ+MB. Altered levels of dopamine and metabolites and reductions in TH immunoreactivity were generally only

Acknowledgements

This study was supported in part by ES05017, ES05903 and ES01247 from the National Institute of Environmental Health Sciences (D. C-S.) and Department of Defense grant DAM D17-98-1-8628 (E.K.R). Special thanks to Drs. Howard J. Federoff, Thomas Gasiewicz and Bernard Weiss for their thoughtful comments and to Dr. Kenneth Olden for his support.

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