Dopaminergic neurotoxicity ofS‐ethylN,N‐dipropylthiocarbamate (EPTC), molinate, andS‐methyl‐N,N‐diethylthiocarbamate (MeDETC) inCaenorhabditis elegans

Abstract

Epidemiological studies corroborate a correlation between pesticide use and Parkinson’s disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S-methyl-N,N-diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. Additionally, worms treated with the three test compounds showed a drastic loss of DAergic-dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD.

Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin

“…Additionally, MND-induced changes in the hTTR PTPM pattern were mostly reversed by NAC. These findings are consistent with previous studies in which NAC supplementation of C. elegans increased the resistance to environmental stressors4445. Additionally, cell culture based studies have shown that the antioxidant NAC effectively protected against MND-induced oxidative stress4647.…”

“…The C. elegans strains were propagated at 20 °C on Nematode Growth Medium (NGM) plates or 8 P plates seeded with either Escherichia coli strain OP50 or NA22, respectively. Synchronous L1 populations were obtained by treating worms with an alkaline bleach solution (1% NaClO and 0.25 M NaOH)45. L1 larvae were placed on OP50-seeded NGM plates after hatching and experiments were performed using L4 stage nematodes unless otherwise noted.…”

Aldehyde dehydrogenase inhibition generates a reactive dopamine metabolite autotoxic to dopamine neurons

“…Results of recent work demonstrate thiocarbamate pesticides to be toxic to DA neurons and implicate these pesticides as potential risk factors for PD [22]. The thiocarbamate molinate was found to an inhibitor of ALDH, and more specifically, molinate and its sulfoxide and sulfone metabolites were found to inactivate human ALDH2 [23,24].…”

Elemental bioimaging of Cisplatin in Caenorhabditis elegans by LA-ICP-MS

“…(Caenorhabditis Genetics Center, CGC). To obtain a synchronous population, worms were treated with an alkaline bleach solution (1% NaOCl and 0.25 M NaOH) as described 39 . Synchronized L1 worms were placed on OP50-seeded NGM plates after hatching and experiments were performed using L4 stage nematodes.…”