The role of skn-1 in methylmercury-induced latent dopaminergic neurodegeneration

Ebany J. Martinez-Finley, Samuel Caito, James C. Slaughter, Michael Aschner

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Mercury (Hg) is a persistent environmental bioaccumulative metal, with developmental exposure to methylmercury (MeHg) resulting in long-term health effects. We examined the impact of early-life exposure to MeHg and knockdown of skn-1 on dopaminergic (DAergic) neurodegeneration in the nematode Caenorhabditis elegans. SKN-1, a the major stress-activated cytoprotective transcription factors, promotes the transcription of enzymes that scavenge free radicals, synthesizes glutathione and catalyzes reactions that increase xenobiotic excretion. Deletions or mutations in this gene suppress stress resistance. Thus, we hypothesized that the extent of MeHg's toxicity is dependent on intact skn-1 response; therefore skn-1 knockout (KO) worms would show heightened sensitivity to MeHg-induced toxicity compared to wildtype worms. In this study we identified the impact of early-life MeHg exposure on Hg content, stress reactivity and DAergic neurodegeneration in wildtype, and skn-1KO C. elegans. Hg content, measured by Inductively Coupled Plasma Mass Spectrometry, showed no strain-dependent differences. Reactive oxygen species generation was dramatically increased in skn-1KO compared to wildtype worms. Structural integrity of DAergic neurons was microscopically assessed by visualization of fluorescently-labeled neurons, and revealed loss of neurons in skn-1KO and MeHg exposed worms compared to wildtype controls. Dopamine levels detected by High-performance liquid chromatography, were decreased in response to MeHg exposure and decreased in skn-1KO worms, and functional behavioral assays showed similar findings. Combined, these studies suggest that knockdown of skn-1 in the nematode increases DAergic sensitivity to MeHg exposure following a period of latency.

Original languageEnglish (US)
Pages (from-to)2650-2660
Number of pages11
JournalNeurochemical Research
Volume38
Issue number12
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

Keywords

  • DAergic neurodegeneration
  • Early-life exposure
  • Methylmercury
  • NRF2
  • skn-1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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