The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice

Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD, aka dioxin; 20 µg/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant; whether these effects are driven by AhR activation in β-cells requires investigation. Here we exposed female and male β-cell specific AhR knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 µg/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from β-cells increased insulin secretion ex vivo in female mouse islets and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice. Our study demonstrates that AhR signaling in β-cell is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both female and male mice, suggesting that the effects of TCDD on β-cell function/health are driving metabolic phenotypes in peripheral tissues. ### Competing Interest Statement The authors have declared no competing interest. * AhR : Aryl hydrocarbon receptor CO : Corn oil Cyp1a1 : Cytochrome P450 1A1 GTT : Glucose tolerance test GSIS : Glucose-stimulated insulin secretion Gsta1 : Glutathione S-transferase alpha 1 Il-1β : Interleukin-1β ITT : Insulin tolerance test Nqo1 : NAD(P)H: quinone oxidoreductase POPs : Persistent Organic Pollutants Ppargc1a : Peroxisome proliferative activated receptor 1α TCDD : 2,3,7,8-tetrachlorodibenzo-p-dioxin T2D : Type 2 diabetes