Transcriptomic profile analysis of brain inferior colliculus following acute hydrogen sulfide exposure

Abstract

Hydrogen sulfide (H₂S) is a gaseous molecule found naturally in the environment, and as an industrial byproduct, and is known to cause acute death and induces long-term neurological disorders following acute high dose exposures. Currently, there is no drug approved for treatment of acute H₂S-induced neurotoxicity and/or neurological sequelae. Lack of a deep understanding of pathogenesis of H₂S-induced neurotoxicity has delayed the development of appropriate therapeutic drugs that target H₂S-induced neuropathology. RNA sequencing analysis was performed to elucidate the cellular and molecular mechanisms of H₂S-induced neurodegeneration, and to identify key molecular elements and pathways that contribute to H₂S-induced neurotoxicity. C57BL/6J mice were exposed by whole body inhalation to 700 ppm of H₂S for either one day, two consecutive days or 4 consecutive days. Magnetic resonance imaging (MRI) scan analyses showed H₂S exposure induced lesions in the inferior colliculus (IC) and thalamus (TH). This mechanistic study focused on the IC. RNA Sequencing analysis revealed that mice exposed once, twice, or 4 times had 283, 193 and 296 differentially expressed genes (DEG), respectively (q-value < 0.05, fold-change> 1.5). Hydrogen sulfide exposure modulated multiple biological pathways including unfolded protein response, neurotransmitters, oxidative stress, hypoxia, calcium signaling, and inflammatory response in the IC. Hydrogen sulfide exposure activated PI3K/Akt and MAPK signaling pathways. Pro-inflammatory cytokines were shown to be potential initiators of the modulated signaling pathways following H₂S exposure. Furthermore, microglia were shown to release IL-18 and astrocytes released both IL-1β and IL-18 in response to H₂S. This transcriptomic analysis data revealed complex signaling pathways involved in H₂S-induced neurotoxicity and may provide important associated mechanistic insights.

Keywords: Brain injury; Hydrogen sulfide; MRI analysis; Neurodegeneration; RNA-seq analysis; Transcriptomic analysis.