Ching, M. E. A.; Hoyeck, M. P.; Basu, L.; Palaniyandi, J.; Grieco-St-Pierre, L.; Tejani, R.; van Zyl, E.; Kostianets, A.; Poleo-Giordani, E.; Bruin, J. E.

Objective: The aryl hydrocarbon receptor (AhR) pathway primarily mediates pollutant responses by activating xenobiotic metabolism enzymes like cytochrome P450 1A1 and 1A2 (CYP1A). Although AhR has also been implicated in systemic metabolic dysfunction and is inducible in pancreatic islets, its role in islet physiology remains unclear. Methods: We analyzed a publicly available bulk human islet transcriptomic dataset to identify pathways associated with CYP1A1 expression. We also assessed islet responses to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and glucolipotoxicity (GLT) in vitro using two mouse models: a global Cyp1a1/1a2 double knockout (CypKO) model, which disrupts canonical AhR-CYP1A signaling in whole islets, and a beta-cell-specific Ahr knockout (betaAhrKO) model, which abolishes AhR signaling selectively in beta-cells. We then examined the role of beta-cell Ahr in early adaptation to high-fat diet (HFD) feeding in vivo. Results: Xenobiotic and nutrient metabolism pathways were enriched in donors with high CYP1A1 expression. Global Cyp1a1/1a2 deletion increased susceptibility of female mouse islets to TCDD-induced impairments in insulin secretion but had minimal effects on GLT responses in either sex. In contrast, beta-cell Ahr deletion did not affect islet responses to TCDD, but exacerbated GLT-induced islet dysfunction in male islets and increased baseline insulin secretion in both vehicle- and GLT-exposed female islets in vitro. Lastly, beta-cell Ahr deletion prevented adaptive HFD-induced hyperinsulinemia in both sexes in vivo. Conclusion: Islet AhR signaling shapes responses to chemical and nutrient stressors in a context- and sex-dependent manner. While the canonical AhR-CYP1A axis supports female islet resilience to TCDD, beta-cell AhR signaling more broadly regulates nutrient stress responses in both sexes.