title: Dopaminergic neurotoxicity of S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, and S-methyl-N,N-diethylthiocarbamate (MeDETC) in Caenorhabditis 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. In addition, 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.
authors.affiliation: Division of Clinical Pharmacology and Pediatric Toxicology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: Caito
authors.forename: William M
authors.initials: WM
authors.lastname: Valentine
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D001381:Azepines / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects*; D059329:Cholinergic Neurons / Q000166:cytology / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D007928:Lethal Dose 50; D018384:Oxidative Stress; D013859:Thiocarbamates / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001381:Azepines; D004785:Environmental Pollutants; D006540:Herbicides; D013859:Thiocarbamates; C070631:S-methyl diethylthiocarbamate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C009821:molinate; D004298:Dopamine
keywords: C. elegans; EPTC; dopamine; molinate; neurodegeneration; pesticide