Abstract
Hydrogen sulfide (H(2)S) 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 H(2)S-induced neurotoxicity and/or neurological sequelae. Lack of a deep understanding of pathogenesis of H(2)S-induced neurotoxicity has delayed the development of appropriate therapeutic drugs that target H(2)S-induced neuropathology. RNA sequencing analysis was performed to elucidate the cellular and molecular mechanisms of H(2)S-induced neurodegeneration, and to identify key molecular elements and pathways that contribute to H(2)S-induced neurotoxicity. C57BL/6J mice were exposed by whole body inhalation to 700 ppm of H(2)S for either one day, two consecutive days or 4 consecutive days. Magnetic resonance imaging (MRI) scan analyses showed H(2)S 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 H(2)S exposure. Furthermore, microglia were shown to release IL-18 and astrocytes released both IL-1β and IL-18 in response to H(2)S. This transcriptomic analysis data revealed complex signaling pathways involved in H(2)S-induced neurotoxicity and may provide important associated mechanistic insights.