It has become increasingly apparent that environmental risk factors must play a role in Parkinson's Disease (PD), a neurodegenerative condition damaging the nigrostriatal dopamine (DA) system. Efforts to confirm an involvement of the herbicide paraquat, a compound with structural similarity to the DA neurotoxicant, MPTP that produces a PD-like syndrome in humans, have not proven compelling. Paraquat, however, shares extensive geographical overlap in use with other agrichemicals, particularly dithlocarbamate and triazole fungicides also known to adversely impact DA systems, suggesting that multiple-hit or combined exposure models may be more realistic with respect to human environmental exposure. Indeed, studies in the investigators' laboratory demonstrate that combined administration of the dithiocarbamate fungicide, maneb (MB) with paraquat (PQ) mice result in potentiated effects on DA function and associated behaviors, relative to vehicle and to either compound administered alone. Moreover, combined PQ and MB appears to preferentially target the nigrostriatal DA system, resulting in both a sustained reduction in tyrosine hydroxylase and in gliosis in the dorsal striatum. These effects occurred at low doses with limited duration of exposure, and in the absence of body weight loss or lung pathology. Thus, combined PQ and MB appears to cause neurotoxicity to the nigrostriatal DA system that is similar to PD and may represent viable environmental risk factor for this disease.
The aims of this proposal are to determine the validity of these agents as an environmental model of PD by examining: 1) the extent to which these behavioral, neurochemical and neuropathological effects mimic those of PD; 2) the extent to which such effects generalize to other combinations of these classes of chemicals and thus the potential scope of the environmental problem; 3) the persistence versus reversibility of these adverse effects, and the extent to which the effects of combined PQ and MB are modulated by; 4) the genetic predisposition, specifically with gender and with over-expression of the protein, alpha-synuclein, thought to play a role in familial and sporadic PD; and, 5) whether exposures during early development or advanced age contribute to enhanced toxicity. 11 Determination of the validity and generality of this combined exposure model would set the stage for significant new research directions aimed at understanding mechanisms, therapeutic strategies, genetic background and the role of development and aging on environmental exposures as a cause of PD. The investigators' findings to date with combined PQ and MB already raise significant concerns about the adequacy of current risk assessment paradigms based on exposures to single compounds and emphasize the urgent need to obtain data on human exposures to these classes of agents.
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