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

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 (C. elegans). SKN-1, a the major stress-activated cytoprotective transcription factors, promotes the transcription of enzymes that scavenge free radicals, synthesizes glutathione (GSH) 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 (ICP-MS), showed no strain-dependent differences. Reactive oxygen species (ROS) 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 (HPLC), 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.

Recent Advances in Mercury Research

“…Studies in Caenorhabditis elegans conducted by Martinez-Finley and colleagues have shown a latency period for neurodegeneration in combination with susceptibility of genetic background [41, 42]. The first study described the impact of early-life exposure to MeHg and knockdown of skn - 1 , the major stress-activated cytoprotective transcription factor, on dopaminergic (DAergic) neurodegeneration, mercury content, and stress reactivity in the nematode C. elegans .…”

“…Dopamine-related behavior in the worms was decreased in response to MeHg exposure and was decreased in skn - 1 KO worms; both were apparent only after a period of latency. Combined, these studies suggest that knockdown of skn - 1 in the nematode increases DAergic sensitivity to MeHg exposure following a period of latency [41]. …”

Toxicity of organic and inorganic mercury species in differentiated human neurons and human astrocytes

“…Previous studies have demonstrated similar toxicities of EtHg and MeHg in brain-associated cells, whereas inorganic Hg induced effects were restricted to substantially higher concentrations [14,15]. Disturbance of neuronal function is accompanied with altered functions specific for certain neurotransmitters such as glutamate and dopamine [16,17]. Nevertheless, numerous studies are limited to the use of immature, proliferating neurons [8,9,11,18,19] or neurons during differentiation [20][21][22] to investigate developmental neurotoxicity.…”

Guarana (Paullinia cupana Mart.) attenuates methylmercury-induced toxicity in Caenorhabditis elegans

“…Skn-1 (ok2315) worms were more sensitive to MeHg than WT worms, as previously described (36, 37). SKN-1 is the ortholog of mammalian Nrf2, a leucine zipper class transcription factor that regulates a number of detoxifying enzymes, including glutathione-S-transferases, and is involved in cellular detoxification and stress response (38, 39).…”

“…SKN-1 is the ortholog of mammalian Nrf2, a leucine zipper class transcription factor that regulates a number of detoxifying enzymes, including glutathione-S-transferases, and is involved in cellular detoxification and stress response (38, 39). The skn-1 (ok2315) mutant strain is more susceptible to environmental stresses (36, 40). The LD50 of MeHg in WT worms treated with GEE were not significantly different compared to GEE-untreated worms.…”