Environmental Risk Factors and the Parkinson's Disease Phenotype

The absence of any compelling data for a solely genetic etiology for Parkinson's disease has focused attention on environmental exposures as causative agents, and the interaction of environmental risk factors in conjunction with a genetic predisposition or aging, the other risk factor associated with Parkinson's disease. The herbicide paraquat has surfaced as a primary candidate for such exposure. This is based on its structural similarity to MPP+, the active metabolite responsible for the neurotoxic effects of MPTP, a neurotoxin, found to induce Parkinsonian-like features in rodents, non-human primates and humans. This restricted focus on paraquat, however, has virtually ignored the fact that human exposure to agricultural chemicals is not to isolated compounds but to mixtures. In fact, one such compound is maneb, (manganese-ethylene-bis-dithio-carbamate) a class of dithiocarbamate fungicides used frequently on crops in conjunction with paraquat.

We have thus developed a combined exposure model using paraquat and maneb. Chronic exposure to the combination produces potentiated decreases in behavior, striatal neurochemistry, and dopaminergic neurons compared to either compound alone. The neurotoxic effects seem to be very selective for the nigrostriatal dopaminergic system. Furthermore, our data indicate that the combined exposure to paraquat and maneb 1) produce an age-related effect, with older animals being more vulnerable; 2) show an increased susceptibility in the presence of a genetic predisposition, in this case a-synuclein; 3) exhibit permanent and even progressive effects associated with developmental exposure and 4) display gender differences. Acting by different underlying mechanisms, combined exposures to maneb and paraquat may be illustrative of the so-called "two-hit" model of disease. This hypothesis holds tremendous implications for further understanding the possible involvement of environmental factors as risk factors in the pathogenesis of Parkinson's disease as well as for the derivation of risk assessment guidelines for human exposures to these compounds.

Our current efforts are focused on trying to determine and understand the mechanisms of neurotoxicity associated with these pesticides and their interaction with the various risk factors associated with Parkinson's disease. Identifying target sites of action will allow for better therapeutic interventions.

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	Age-related and irreversible nigrostriatal dopaminergic neurotoxicity of combined exposure to paraquat and maneb. Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slecta DA (2003). Eur J Neurosci. Aug. 18(3): 589-600.
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