Mammalian AHR2 loss: Evolutionary patterns, mechanisms, and relevance of biological factors

Environmental contamination by dioxins and polycyclic aromatic hydrocarbons threatens wildlife health, yet the molecular basis of interspecies variation in toxicological sensitivity remains poorly understood. The aryl hydrocarbon receptor (AHR) mediates dioxin-like responses and typically exists as two isoforms (AHR1 and AHR2) across vertebrates but mammals exhibit a unique evolutionary restructuring characterized by widespread loss of AHR2. To elucidate the evolutionary patterns and mechanisms underlying mammalian AHR2 loss and its relevance to interspecies pollutant sensitivity, we analyzed AHR2 retention, expression, and function across 220 mammalian species. AHR2 was retained in only 29 % of species, restricted to marsupials and select placental lineages (Felidae, Perissodactyla, Proboscidea, and Pinnipedia), contrasting sharply with universal multi-isoform retention in other vertebrates. Retention declined from 100 % in monotremes to 17.1 % in derived placentals, coinciding with placental evolution. Even where retained, AHR2 expression was negligible across tissues (