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The Role of skn-1 in Methylmercury-Induced Latent Dopaminergic Neurodegeneration

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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.

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Acknowledgments

This manuscript was supported by the National Institute of Environmental Health Sciences (NIEHS) [R01ES07331, T32ES007028] and the National Institutes of Health Loan Repayment Program. We would like to acknowledge the Caenorhabditis Genetic Center (CGC), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440), for providing the strains used in this manuscript.

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Authors and Affiliations

  1. Division of Pediatric Toxicology and Clinical Pharmacology, Vanderbilt University Medical Center, 11425 MRB IV, 2215-B Garland Ave., Nashville, TN, 37232-0414, USA

    Ebany J. Martinez-Finley, Samuel Caito & Michael Aschner

  2. Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA

    Ebany J. Martinez-Finley, Samuel Caito & Michael Aschner

  3. Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA

    Ebany J. Martinez-Finley & Samuel Caito

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    James C. Slaughter

  5. Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN, USA

    Michael Aschner

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  1. Ebany J. Martinez-Finley
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  2. Samuel Caito
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  4. Michael Aschner
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Correspondence to Michael Aschner.

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Martinez-Finley, E.J., Caito, S., Slaughter, J.C. et al. The Role of skn-1 in Methylmercury-Induced Latent Dopaminergic Neurodegeneration. Neurochem Res 38, 2650–2660 (2013). https://doi.org/10.1007/s11064-013-1183-0

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