The nigrostriatal dopaminergic system as a preferential target of repeatedexposures to combined paraquat and maneb: Implications for Parkinson's disease

Experimental evidence supporting 1,1'-dimethyl-4,4'-bipyridinium [paraquat (PQ)] as a risk factor for Parkinson's disease (PD) is equivocal. Other agr icultural chemicals, including dithiocarbamate fungicides such as manganese ethylenebisdithiocarbamate [maneb (MB)], are widely used in the same geogr aphical regions as paraquat and also impact dopamine systems, suggesting th at mixtures may be more relevant etiological models. This study therefore p roposed that combined PQ and MB exposures would produce greater effects on dopamine (DA) systems than would either compound administered alone. Male C 57BL/6 mice were treated twice a week for 6 weeks with intraperitoneal sali ne, 10 mg/kg paraquat, 30 mg/kg maneb, or their combination (PQ 1 MB). MB, but not PQ, reduced motor activity immediately after treatment, and this ef fect was potentiated by combined PQ 1 MB treatment. As treatments progresse d, only the combined PQ 1 MB group evidenced a failure of motor activity le vels to recover within 24 hr. Striatal DA and dihydroxyphenylacetic acid in creased 1-3 d and decreased 7 d after injections. Only PQ 1 MB reduced tyro sine hydroxylase (TH) and DA transporter immunoreactivity and did so in dor sal striatum but not nucleus accumbens. Correspondingly, striatal TH protei n levels were decreased only by combined PQ 1 MB 5 d after injection. React ive gliosis occurred only in response to combined PQ 1 MB in dorsal-medial but not ventral striatum. TH immunoreactivity and cell counts were reduced only by PQ 1 MB and in the substantia nigra but not ventral tegmental area. These synergistic effects of combined PQ 1 MB, preferentially expressed in the nigrostriatal DA system, suggest that such mixtures could play a role in the etiology of PD.