Hydrogen sulfide (H₂S) poisoning remains a significant source of occupational fatalities and is the second most common cause of toxic gas-induced deaths. It is a rapidly metabolized systemic toxicant targeting the mitochondria, among other organelles. Intoxication is mostly acute, but chronic or in-between exposure scenarios also occur. Some genetic defects in H₂S metabolism lead to lethal chronic H₂S poisoning. In acute exposures, the neural, respiratory, and cardiovascular systems are the primary target organs resulting in respiratory distress, convulsions, hypotension, and cardiac irregularities. Some survivors of acute poisoning develop long-term sequelae, particularly in the central nervous system. Currently, treatment for H₂S poisoning is primarily supportive care as there are no FDA-approved drugs. Besides hyperbaric oxygen treatment, drugs in current use for the management of H₂S poisoning are controversial. Novel potential drugs are under pre-clinical research development, most of which target binding the H₂S. However, there is an acute need to discover new drugs to prevent and treat H₂S poisoning, including reducing mortality and morbidity, preventing sequalae from acute exposures, and for treating cumulative pathology from chronic exposures. In this paper, we perform a comprehensive review of H₂S poisoning including perspectives on past, present, and future.

Hydrogen sulfide (H₂S) is a highly neurotoxic gas. Acute exposure can lead to neurological sequelae among survivors. A drug for treating neurological sequelae in survivors of acute H₂S intoxication is needed. Using a novel mouse model we evaluated the efficacy of cobinamide (Cob) for increasing survival of, and reducing neurological sequalae in, mice exposed to sublethal doses of H₂S. There were two objectives: (1) to determine the dose–response efficacy of Cob and (2) to determine the effective therapeutic time window of Cob. To explore objective 1, mice were injected intramuscularly with Cob at 0, 50, or 100 mg/kg at 2 min after H₂S exposure. For objective 2, mice were injected intramuscularly with 100 mg/kg Cob at 2, 15, and 30 min after H₂S exposure. For both objectives, mice were exposed to 765 ppm of H₂S gas. Cob significantly reduced H₂S‐induced lethality in a dose‐dependent manner (P < 0.05). Cob‐treated mice exhibited significantly fewer seizures and knockdowns compared with the H₂S‐exposed group. Cob also reversed H₂S‐induced weight loss, behavioral deficits, neurochemical changes, cytochrome c oxidase enzyme inhibition, and neurodegeneration in a dose‐ and time‐dependent manner (P < 0.01). Overall, these findings show that Cob increases survival and is neuroprotective in a mouse model of H₂S‐induced neurological sequelae.

Acute exposure to high concentrations of hydrogen sulfide (H₂S) leads to sudden death and, if survived, lingering neurological disorders. Clinical signs include seizures, loss of consciousness, and dyspnea. The proximate mechanisms underlying H₂S-induced acute toxicity and death have not been clearly elucidated. We investigated electrocerebral, cardiac, and respiratory activity during H₂S exposure using electroencephalogram (EEG), electrocardiogram, and plethysmography. H₂S suppressed electrocerebral activity and disrupted breathing. Cardiac activity was comparatively less affected. To test whether Ca²⁺ dysregulation contributes to H₂S-induced EEG suppression, we developed an in vitro real-time rapid throughput assay measuring patterns of spontaneous synchronized Ca²⁺ oscillations in cultured primary cortical neuronal networks loaded with the indicator Fluo-4 using the fluorescent imaging plate reader (FLIPR-Tetra^®). Sulfide >5 ppm dysregulated synchronous calcium oscillation (SCO) patterns in a dose-dependent manner. Inhibitors of NMDA and AMPA receptors magnified H₂S-induced SCO suppression. Inhibitors of L-type voltage-gated Ca²⁺ channels and transient receptor potential (TRP) channels prevented H₂S-induced SCO suppression. Inhibitors of T-type voltage-gated Ca²⁺ channels, ryanodine receptors, and sodium channels had no measurable influence on H₂S-induced SCO suppression. Exposures to >5 ppm sulfide also suppressed neuronal electrical activity in primary cortical neurons measured by multielectrode array (MEA), an effect alleviated by pretreatment with the nonselective TRP channel inhibitor, 2-aminoethoxydiphenylborate (2-APB). 2-APB also reduced primary cortical neuronal cell death from sulfide exposure. These results improve our understanding of the role of different Ca²⁺ channels in acute H₂S-induced neurotoxicity and identify TRP channel modulators as novel structures with potential therapeutic benefits.

Hydrogen sulfide (H₂S) is a toxin affecting the cardiovascular, respiratory, and central nervous systems. Acute H₂S exposure is associated with a high rate of mortality and morbidity. The precise pathophysiology of H₂S-induced death is a controversial topic; however, inhibition of the respiratory center in the brainstem is commonly cited as a cause of death. There is a knowledge gap on toxicity and toxic mechanisms of acute H₂S poisoning on the brainstem, a brain region responsible for regulating many reflective and vital functions. Serotonin (5-HT), dopamine (DA), and γ-aminobutyric acid (GABA) play a role in maintaining a normal stable respiratory rhythmicity. We hypothesized that the inhibitory respiratory effects of H₂S poisoning are mediated by 5-HT in the respiratory center of the brainstem. Male C57BL/6 mice were exposed once to an LCt₅₀ concentration of H₂S (1000 ppm). Batches of surviving mice were euthanized at 5 min, 2 h, 12 h, 24 h, 72 h, and on day 7 post-exposure. Pulmonary function, vigilance state, and mortality were monitored during exposure. The brainstem was analyzed for DA, 3,4-dehydroxyphenyl acetic acid (DOPAC), 5-HT, 5-hydroxyindoleatic acid (5-HIAA), norepinephrine (NE), GABA, glutamate, and glycine using HPLC. Enzymatic activities of monoamine oxidases (MAO) were also measured in the brainstem using commercial kits. Neurodegeneration was assessed using immunohistochemistry and magnetic resonance imaging. Results showed that DA and DOPAC were significantly increased at 5 min post H₂S exposure. However, by 2 h DA returned to normal. Activities of MAO were significantly increased at 5 min and 2 h post-exposure. In contrast, NE was significantly decreased at 5 min and 2 h post-exposure. Glutamate was overly sensitive to H₂S-induced toxicity manifesting a time-dependent concentration reduction throughout the 7 day duration of the study. Remarkably, there were no changes in 5-HT, 5-HIAA, glycine, or GABA concentrations. Cytochrome c oxidase activity was inhibited but recovered by 24 h. Neurodegeneration was observed starting at 72 h post H₂S exposure in select brainstem regions. We conclude that acute H₂S exposure causes differential effects on brainstem neurotransmitters. H₂S also induces neurodegeneration and biochemical changes in the brainstem. Additional work is needed to fully understand the implications of both the short- and long-term effects of acute H₂S poisoning on vital functions regulated by the brainstem.

The risk of accidental bromine (Br₂) exposure to the public has increased due to its enhanced industrial use. Inhaled Br₂ damages the lungs and the heart; however, adverse effects on the brain are unknown. In this study, we examined the neurological effects of inhaled Br₂ in Sprague Dawley rats. Rats were exposed to Br₂ (600 ppm for 45 min) and transferred to room air and cage behavior, and levels of glial fibrillary acidic protein (GFAP) in plasma were examined at various time intervals. Bromine exposure resulted in abnormal cage behavior such as head hitting, biting and aggression, hypervigilance, and hyperactivity. An increase in plasma GFAP and brain 4-hydroxynonenal (4-HNE) content also was observed in the exposed animals. Acute and delayed sympathetic nervous system activation was also evaluated by assessing the expression of catecholamine biosynthesizing enzymes, tryptophan hydroxylase (TrpH1 and TrpH2), and tyrosine hydroxylase (TyrH), along with an assessment of catecholamines and their metabolites. TyrH was found to be increased in a time-dependent manner. TrpH1 and TrpH2 were significantly decreased upon Br₂ exposure in the brainstem. The neurotransmitter content evaluation indicated an increase in 5-HT and dopamine at early timepoints after exposure; however, other metabolites were not significantly altered. Taken together, our results predict brain damage and autonomic dysfunction upon Br₂ exposure.

Hydrogen sulfide (H₂S) is common in concentrated pig feed operations from the decomposition of manure. Ambient H₂S is a respiratory tract irritant and an environmental stressor for caretakers and pigs. Influenza A virus (IAV), a zoonotic pathogen, has caused prior pandemics. The effects of H₂S or IAV alone on the respiratory system have been investigated, but their interaction has not. We hypothesized that exposure to environmentally-relevant H₂S concentrations increases the pathogenicity of IAV infection in swine. Thirty-five, three-week old pigs of mixed sex were exposed to breathing air or H₂S via inhalation 6 hours daily for 12 days. After 7 days, pigs were inoculated with H3N2 IAV (or a placebo). Results showed that ambient H₂S increased the severity of respiratory distress and lung pathology. H₂S also suppressed IL-IL-1β, IL-6 and IL-8 cytokine response in BALF and increased viral loads and nasal shedding.