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 (<0.1 % of total AHR). Ligand-responsive reporter assays showed that mammalian AHR1 exhibits 10-50-fold greater transactivation potency than AHR2 for both TCDD and the endogenous ligand kynurenine, indicating adaptive enhancement of AHR1 responsiveness. Machine learning analysis of 104 ecological variables identified elevated mass-specific metabolic rate and small body size as strong correlates of AHR2 loss. These patterns are consistent with selective pressures arising from competition for the shared ARNT co-factor under placental kynurenine signaling and metabolic or hypoxic stress, rendering the functionally inferior AHR2 selectively disadvantageous. The transition to a single-isoform AHR system reflects evolutionary optimization under physiological constraints and provides a mechanistic framework for predicting species-specific pollutant sensitivity in mammals.