Recent studies suggest that exposure to
agrochemicals may contribute to the development of
idiopathic Parkinson's disease.
Maneb (MB), a widely used Mn-containing
ethylene-bis-dithiocarbamate (EBDC) fungicide, has been implicated in selective dopaminergic neurotoxicity. In this study, we examine the potential neurotoxicity of
mancozeb (MZ), a widely used EBDC fungicide that is structurally similar to MB, but contains both Zn and Mn. Primary mesencephalic cells isolated from Sprague-Dawley embryonic day 15 rat embryos were exposed in vitro to either MZ or MB to compare their cytotoxic potential. Exposure to 10-120 microM MZ or MB for 24h resulted in a dose-dependent toxicity in both the
dopamine (DA) and
GABA mesencephalic populations as assessed by a functional assay for high affinity transporter activity. Consistent with this, cell viability as well as
tyrosine hydroxylase-positive neurons decreased with increasing doses of MZ or MB. Toxic potencies for MZ and MB were similar and no difference in sensitivity between the DA and
GABA populations was observed with the fungicides. Exposure to
ethylene thiourea, the major metabolite of either MZ or MB, was not toxic, implicating the parent compound in toxicity. Both the organic and Mn
metal components of the fungicides were found to contribute to toxicity. Non-toxic exposures to the fungicides decreased
ATP levels in a dose-dependent manner suggesting impairment of energy metabolism. In whole mitochondrial preparations isolated from adult rat brains, MZ and MB inhibited
NADH-linked state 3 respiration. Mild to moderate mitochondrial uncoupling was also observed in response to the fungicides. In conclusion, our findings indicate that acute exposure to high doses of MZ and MB produce equipotent toxic effects in both DA and GABA neurons that may be associated with perturbations in mitochondrial respiration.