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

The absence of any compelling basis for a heritable basis of idiopathic Par kinson's disease (PD) has focused attention on environmental exposures as c ausative agents. While the herbicide paraquat has repeatedly been implicate d, 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 dopam ine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraqu at and maneb would produce additive effects and support a multiple-hit envi ronmental 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 wee k for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with ac tivity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediatel y 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 expo sure and were detected in dorsal striatum, but not in the nucleus accumbens . The fact that combined exposures resulted in potentiated effects that app ear to target nigrostriatal dopamine systems suggests that these combinatio ns may be important environmental risk factors for Parkinsonism. These find ings also raise questions about the adequacy of current risk assessment gui delines for these chemicals which are based on effect levels derived from e xposures to single agents. (C) 2000 Elsevier Science B.V. All rights reserv ed.