Metabolomic Signatures of Brainstem in Mice following Acute and Subchronic Hydrogen Sulfide Exposure.

Hydrogen sulfide (H2S) is an environmental toxicant of significant health concern. The brain is a major target in acute H2S poisoning. This study was conducted to test the hypothesis that acute and subchronic ambient H2S exposures alter the brain metabolome. Male 7-8-week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H2S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H2S 2 h/day, 5 days/week for 5 weeks. Control mice were exposed to room air. The brainstem was removed for metabolomic analysis. Enrichment analysis showed that the metabolomic profiles in acute and subchronic H2S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer's disease. Acute H2S exposure decreased excitatory neurotransmitters, aspartate, and glutamate, while the inhibitory neurotransmitter, serotonin, was increased. Branched-chain amino acids and glucose were increased by acute H2S exposure. Subchronic H2S exposure within OSHA guidelines surprisingly decreased serotonin concentration. In subchronic H2S exposure, glucose was decreased, while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues for acute and subchronic ambient H2S poisoning and show that H2S alters brainstem metabolome.

Acute hydrogen sulfide-induced neurochemical and morphological changes in the brainstem.

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.

A comprehensive review of treatments for hydrogen sulfide poisoning: past, present, and future.

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.

Pre-exposure to hydrogen sulfide modulates the innate inflammatory response to organic dust.

Animal production units produce and store many contaminants on-site, including organic dust (OD) and hydrogen sulfide (H2S). Workers in these settings report various respiratory disease symptoms. Both OD and H2S have shown to induce lung inflammation. However, impact of co-exposure to both H2S and OD has not been investigated. Therefore, we tested a hypothesis that pre-exposure to H2S modulates the innate inflammatory response of the lungs to organic dust. In a mouse model of H2S and organic dust extract (ODE) exposure, we assessed lung inflammation quantitatively. We exposed human airway epithelial and monocytic cells to medium or H2S alone or H2S followed by ODE and measured cell viability, oxidative stress, and other markers of inflammation. Exposure to 10 ppm H2S followed by ODE increased the lavage fluid leukocytes. However, exposure to 10 ppm H2S alone resulted in changes in tight junction proteins, an increase in mRNA levels of tlr2 and tlr4 as well as ncf1, ncf4, hif1α, and nrf2. H2S alone or H2S and ODE exposure decreased cell viability and increased reactive nitrogen species production. ODE exposure increased the transcripts of tlr2 and tlr4 in both in vitro and in vivo models, whereas increased nfkbp65 transcripts following exposure to ODE and H2S was seen only in in vitro model. H2S alone and H2S followed by ODE exposure increased the levels of IL-1ß. We conclude that pre-exposure to H2S modulates lung innate inflammatory response to ODE.