Chronic low-dose dioxin exposure accelerates high fat diet-induced hyperglycemia in female mice

Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin), and increased diabetes risk. We previously showed that acute high-dose (20 ug/kg) TCDD exposure decreased plasma insulin levels in both male and female mice in vivo, however effects on glucose homeostasis were sex-dependent. The current study investigated the impact of chronic low-dose TCDD exposure (20 ng/kg/d, 2x/week) on beta cell function and glucose homeostasis in male and female mice fed either a chow diet or high-fat diet (HFD) for 12 weeks. Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. In addition, islet RNAseq analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females. Our data supports a double-hit hypothesis that TCDD exposure combined with HFD-feeding is more deleterious than either in isolation in female mice, and that chronic TCDD exposure increases diabetes susceptibility in females.