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

• Published in: Chemical research in toxicology 2017-09, Vol.30 (9), p.1673-1684
• Main Authors: Ihara, Hideshi, Kasamatsu, Shingo, Kitamura, Atsushi, Nishimura, Akira, Tsutsuki, Hiroyasu, Ida, Tomoaki, Ishizaki, Kento, Toyama, Takashi, Yoshida, Eiko, Abdul Hamid, Hisyam, Jung, Minkyung, Matsunaga, Tetsuro, Fujii, Shigemoto, Sawa, Tomohiro, Nishida, Motohiro, Kumagai, Yoshito, Akaike, Takaaki
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - immunology; Cell Survival - drug effects; Chromatography, High Pressure Liquid; Cyclic GMP - analogs & derivatives; Cyclic GMP - chemistry; Cyclic GMP - immunology; Cyclic GMP - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Immunohistochemistry; Male; Methylmercury Compounds - analysis; Methylmercury Compounds - chemistry; Methylmercury Compounds - toxicity; Microscopy, Fluorescence; Naphthoquinones - chemistry; Naphthoquinones - toxicity; Nitric Oxide - analysis; Oxidation-Reduction; PC12 Cells; ras Proteins - genetics; ras Proteins - metabolism; Rats; Rats, Wistar; Reactive Oxygen Species - analysis; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Spectrometry, Mass, Electrospray Ionization; Sulfides - chemistry; Sulfides - pharmacology
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/acs.chemrestox.7b00120

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.