Avoidance of hydrogen sulfide is modulated by external and internal states in Caenorhabditis elegans

Hydrogen sulfide (H₂S) acts as an energy source, a toxin, and a gasotransmitter across diverse biological contexts. We use the robust locomotory responses of Caenorhabditis elegans to high levels of H₂S to elucidate the molecular mechanisms underlying its acute and adaptive responses. We find that the H₂S-evoked behavioral response is shaped by multiple environmental factors including oxygen (O₂) levels and nutritional state and is modulated by various pathways such as insulin, TGF-β, and HIF-1 signaling, as well as by input from O₂-sensing neurons. Prolonged exposure to H₂S activates HIF-1 signaling, leading to the upregulation of stress-responsive genes, including those involved in H₂S detoxification. This promotes an adaptive state in which locomotory speed is reduced in H₂S, while responsiveness to other stimuli is preserved. In mutants deficient in HIF-1 signaling, iron storage, and detoxification mechanisms, animals display a robust initial response but rapidly enter a sleep-like behavior characterized by reduced mobility and diminished responsiveness to subsequent sensory stimuli. Furthermore, while acute production of mitochondria-derived reactive O₂ species (ROS) appears to initiate the avoidance response to H₂S, persistently high ROS promotes an adaptive state, likely by activating various stress-response pathways, without substantially compromising cellular H₂S detoxification capacity. Taken together, our study provides comprehensive molecular insights into the mechanisms through which C. elegans modulates and adapts its response to H₂S exposure.