Acute acrylonitrile exposure inhibits endogenous H2S biosynthesis in rat brain and liver: The role of CBS/3-MPST-H2S pathway in its astrocytic toxicity

Bobo Yang, Wenjun Zhao, Changsheng Yin, Yu Bai, Suhua Wang, Guangwei Xing, Fang Li, Jinsong Bian, Michael Aschner, Jiyang Cai, Haifeng Shi, Rongzhu Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Hydrogen sulfide (H2S) as the third gasotransmitter molecule serves various biological regulatory roles in health and disease. Acrylonitrile (AN) is a common occupational toxicant and environmental pollutant, causing brain and liver damage in mammals. The biotransformation of AN is dependent-upon reduced glutathione (GSH), cysteine and other sulfur-containing compounds. However, the effects of AN on the endogenous H2S biosynthesis pathway have yet to be determined. Herein, we demonstrated that a single exposure to AN (at 25, 50, or 75 mg/kg for 1, 6 or 24 h) decreased the endogenous H2S content and H2S-producing capacity in a dose-dependent manner, both in the cerebral cortex and liver of rats in vivo. In addition, the inhibitory effects of AN (1, 2.5, 5, 10 mM for 12 h) on the H2S content and/or the expression of H2S-producing enzymes were also found both in primary rat astrocytes and rat liver cell line (BRL cells). Impairment in the H2S biosynthesis pathway was also assessed in primary rat astrocytes treated with AN. It was found that inhibition of the cystathionine-β-synthase (CBS)/3-mercaptopyruvate sulfurtransferase (3-MPST)-H2S pathway with the CBS inhibitor or 3-MPST-targeted siRNA significantly increased the AN-induced (5 mM for 12 h) cytotoxicity in astrocytes. In turn, CBS activation or 3-MPST overexpression as well as exogenous NaHS supplementation significantly attenuated AN-induced cytotoxicity. Taken together, endogenous H2S biosynthesis pathway was disrupted in rats acutely exposed to AN, which contributes to acute AN neurotoxicity in primary rat astrocytes.

Original languageEnglish (US)
Article number152685
JournalToxicology
Volume451
DOIs
StatePublished - Mar 15 2021

Keywords

  • 3-mercaptopyruvate sulfurtransferase
  • Acrylonitrile
  • Cystathionine-β-synthase
  • Hydrogen sulfide
  • Neurotoxicity

ASJC Scopus subject areas

  • Toxicology

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