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

Hydrogen sulfide (H 2 S) 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 H 2 S to elucidate the molecular mechanisms underlying its acute and adaptive responses. We find that the H 2 S-evoked behavioral response is shaped by multiple environmental factors including oxygen (O 2 ) 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 O 2 -sensing neurons. Prolonged exposure to H 2 S activates HIF-1 signaling, leading to the upregulation of stress-responsive genes, including those involved in H 2 S detoxification. This promotes an adaptive state in which locomotory speed is reduced in H 2 S, 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 O 2 species (ROS) appears to initiate the avoidance response to H 2 S, persistently high ROS promotes an adaptive state, likely by activating various stress-response pathways, without substantially compromising cellular H 2 S detoxification capacity. Taken together, our study provides comprehensive molecular insights into the mechanisms through which C. elegans modulates and adapts its response to H 2 S exposure.