SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity.
Methylmercury (MeHg) exposure from occupational, environmental, and food sources is a significant threat to public health. MeHg poisonings in adults may result in severe psychological and neurological deficits, and in utero exposures can confer embryonic defects and developmental delays. Recent epidemiological and vertebrate studies suggest that MeHg exposure may also contribute to dopamine (DA) neuron vulnerability and the propensity to develop Parkinson's disease (PD). In this study, we describe a Caenorhabditis elegans model of MeHg toxicity that shows that low, chronic exposure confers embryonic defects, developmental delays, decreases in brood size and animal viability, and DA neuron degeneration. Toxicant exposure results in the robust induction of the glutathione-S-transferases (GSTs) gst-4 and gst-38 that are largely dependent on the PD-associated phase II antioxidant transcription factor SKN-1/Nrf2. We also demonstrate that the expression of SKN-1, a protein previously localized to a small subset of chemosensory neurons and intestinal cells in the nematode, is also expressed in the DA neurons, and a reduction in SKN-1 gene expression increases MeHg-induced animal vulnerability and DA neuron degeneration. These studies recapitulate fundamental hallmarks of MeHg-induced mammalian toxicity, identify a key molecular regulator of toxicant-associated whole-animal and DA neuron vulnerability, and suggest that the nematode will be a useful in vivo tool to identify and characterize mediators of MeHg-induced developmental and DA neuron pathologies.
Vanduyn
Natalia
N
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Settivari
Raja
R
Wong
Garry
G
Nass
Richard
R
D000826:Animal Testing Alternatives; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008136:Longevity / Q000187:drug effects; D020262:Mercury Poisoning, Nervous System; D008767:Methylmercury Compounds / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D012098:Reproduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014874:Water Pollutants, Chemical
D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D008767:Methylmercury Compounds; D051267:NF-E2-Related Factor 2; D014157:Transcription Factors; D014874:Water Pollutants, Chemical; C073702:skn-1 protein, C elegans; C004925:methylmercuric chloride; D004298:Dopamine