Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide-induced neurotoxicity and neurological sequelae.

Hydrogen sulfide (H2 S) is a highly neurotoxic gas. It is the second most common cause of gas-induced deaths. Beyond mortality, surviving victims of acute exposure may suffer long-term neurological sequelae. There is a need to develop countermeasures against H2 S poisoning. However, no translational animal model of H2 S-induced neurological sequelae exists. Here, we describe a novel mouse model of H2 S-induced neurotoxicity for translational research. In paradigm I, C57/BL6 mice were exposed to 765 ppm H2 S for 40 min on day 1, followed by 15-min daily exposures for periods ranging from 1 to 6 days. In paradigm II, mice were exposed once to 1000 ppm H2 S for 60 minutes. Mice were assessed for behavioral, neurochemical, biochemical, and histopathological changes. H2 S intoxication caused seizures, dyspnea, respiratory depression, knockdowns, and death. H2 S-exposed mice showed significant impairment in locomotor and coordinated motor movement activity compared with controls. Histopathology revealed neurodegenerative lesions in the collicular, thalamic, and cortical brain regions. H2 S significantly increased dopamine and serotonin concentration in several brain regions and caused time-dependent decreases in GABA and glutamate concentrations. Furthermore, H2 S significantly suppressed cytochrome c oxidase activity and caused significant loss in body weight. Overall, male mice were more sensitive than females. This novel translational mouse model of H2 S-induced neurotoxicity is reliable, reproducible, and recapitulates acute H2 S poisoning in humans.