Structural analogs modulate olfactory and behavioral responses to a bile acid sex pheromone in sea lamprey (Petromyzon marinus)

Male sea lamprey (Petromyzon marinus) release a sex pheromone featuring a potent bile acid 3-keto petromyzonol sulfate (3kPZS), which plays a critical role in attracting ovulated females to spawning sites during their terminal reproductive phase. In this study, we evaluated how systematic modifications of 3kPZS, referred to as the 11 analogs that retain the 3kPZS core structure with one or more functional group substitutions, affect female sea lamprey neurophysiological and behavioral responses to 3kPZS. Using electro-olfactogram recordings and two-choice flume behavioral assays, we characterized responses elicited by each analog and assessed whether the analogs interfered with 3kPZS-induced responses. Our results demonstrate that bile acid analogs with substitutions of hydroxyl or ketone groups with sulfate moieties at carbon positions 3, 7, 12, and 24 elicit distinct olfactory and behavioral responses in sea lamprey. Analogs with a sulfate group at the carbon-24 position tended to elicit potent olfactory responses of comparable magnitude to 3kPZS. Adding more sulfates at the carbon-3, 7, or 12 position altered behavioral valence and often neutralized or reversed female attraction to 3kPZS in a flume. These data elucidate structure-activity relationships and identify key structural determinants underlying sea lamprey olfactory detection and odorant-mediated behavioral responses. The findings may inform a potential approach for managing invasive sea lamprey populations in the Laurentian Great Lakes by disrupting bile acid mediated pheromone communication. Further research is needed to assess the utility of these compounds in natural stream environments and to refine the structural features of these pheromone antagonists to enhance their efficacy.