2. Academic Validation
  3. Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells

Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells

  • Chem Res Toxicol. 2017 Sep 18;30(9):1673-1684. doi: 10.1021/acs.chemrestox.7b00120.
Hideshi Ihara 1,  Shingo Kasamatsu 1 2,  Atsushi Kitamura 1,  Akira Nishimura 2,  Hiroyasu Tsutsuki 3,  Tomoaki Ida 2,  Kento Ishizaki 1,  Takashi Toyama 4,  Eiko Yoshida 4,  Hisyam Abdul Hamid 2 5,  Minkyung Jung 2,  Tetsuro Matsunaga 2,  Shigemoto Fujii 2,  Tomohiro Sawa 3,  Motohiro Nishida 6,  Yoshito Kumagai 4,  Takaaki Akaike 2
Affiliations

Affiliations

  • 1 Department of Biological Science, Graduate School of Science, Osaka Prefecture University , Osaka 599-8531, Japan.
  • 2 Department of Environmental Health Sciences and Molecular Toxicology, Tohoku University Graduate School of Medicine , Sendai 980-8575, Japan.
  • 3 Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University , Kumamoto 860-8556, Japan.
  • 4 Environmental Biology Section, Faculty of Medicine, University of Tsukuba , Tsukuba, Ibaraki 305-8575, Japan.
  • 5 Department of Pharmaceutical Pharmacology and Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA Puncak Alam Campus , 42300 Puncak Alam, Selangor, Malaysia.
  • 6 Division of Cardiocirculatory Signaling, National Institute for Physiological Sciences (Okazaki Institute for Integrative Bioscience), National Institutes of Natural Sciences , Aichi 444-8787, Japan.
PMID: 28837763 DOI: 10.1021/acs.chemrestox.7b00120
Abstract

Electrophiles such as methylmercury (MeHg) affect cellular functions by covalent modification with endogenous thiols. Reactive persulfide species were recently reported to mediate antioxidant responses and redox signaling because of their strong nucleophilicity. In this study, we used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of the endogenous electrophilic molecule 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. In conclusion, exogenous electrophiles such as MeHg with strong electrophilicity impair the redox signaling regulatory mechanism, particularly of intracellular reactive persulfide species and therefore lead to cellular pathogenesis. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating cell injury by electrophiles.

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