Increased synaptosomal dopamine content and brain concentration of paraquat produced by selective dithiocarbamates

Abstract

Exposure to pesticides may be a risk factor for Parkinson's disease based on epidemiologic data in humans, animal models and in vitro studies. Different dithiocarbamate pesticides potentiate the toxicity of both 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine and paraquat in mouse models of Parkinsonism by an unknown mechanism. This study examined the effects of commercially used dithiocarbamates on Increased dopamine accumulation in synaptosomes was dose dependent and was related to the carbon backbone of these molecules. The dithiocarbamates that increased accumulation of dopamine did not alter the influx of dopamine, but rather delayed the efflux out of synaptosomes. These same dithiocarbamates also increased the tissue content of [14 C]paraquat in vivo by a mechanism that appeared to be distinct from the dopamine transporter. There was a consistent relationship between the dithiocarbamates that increased synaptosomal accumulation of dopamine and tissue content of paraquat, with those previously demonstrated to enhance paraquat toxicity in vivo. These results suggest that selective dithiocarbamates may alter the kinetics of different endogenous and exogenous compounds to enhance their neurotoxicity.

A Fetal Risk Factor for Parkinson’s Disease

“…Alternatively, MB may itself indirectly or directly induce a persistent stress on the nigrostriatal dopaminergic neurons, such that they are already compromised and vulnerable when PQ exposure occurs. In vitro evidence suggests that an immediate effect MB is altered toxicokinetics of DA, such that efflux is impeded, thus increasing DA concentration [Barlow et al, 2003]. During development, DA has autocrine and paracrine functions [De Vitry et al, 1991;Levitt et al, 1997], but excess intracellular DA may be oxidized and interfere with mitochondrial function [Berman and Hastings, 1999].…”

Parkinson's disease and pesticides: a toxicological perspective

“…One such combination is that of paraquat and the fungicide maneb. The overlap in geographic usage of these compounds was used as a rationale for animal studies that showed that coexposure caused decreased motor activity, altered striatal dopamine and dopamine metabolites, decreased striatal tyrosine hydroxylase and dopamine transporter (DAT) expression and increased accumulation of dopamine in synaptosomes [18,39,40]. However, the compounds are not used simultaneously [ATSDR -CERCLA Priority List of Hazardous Substances (http://www.atsdr.cdc.gov/cercla)] and, although paraquat does persist in the environment (Figure 4), due to its high affinity for soil it is not biologically available, making such simultaneous exposures unlikely in the human population.…”

Rodent Model of Parkinson’s Disease: Unilateral or Bilateral?

“…A combination of paraquat with another pesticide manganese ethylene-bis-dithiocarbamate (Maneb) is an alternative formula for PD rodent model establishment. The combination increases the concentration of paraquat and enhances the toxicity to the dopaminergic neurons [38][39][40]. Maneb is a fungicide and used independently to induce PD via a similar mechanism to paraquat, which targets on the mitochondrial complex III [41].…”