Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

Objective: 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 TCDD exposure (20 ug/kg) decreased plasma insulin levels in both male and female mice in vivo; however, effects on glucose homeostasis were sex-dependent. The purpose of this study was to determine whether prolonged exposure to a physiologically relevant dose of TCDD impairs beta cell function and/or glucose homeostasis in a sex-dependent manner in either chow-fed or HFD-fed mice. Methods: Male and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks, and simultaneously fed a chow or 45% high-fat diet (HFD). Glucose metabolism was assessed by glucose and insulin tolerance tests throughout the study. Islets were isolated from females at 12 weeks for Tempo-Seq analysis. Results: 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 TempO-Seq analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females. Conclusions: Our data suggest that TCDD exposure is more deleterious when combined with HFD-feeding in female mice, and that low-dose TCDD exposure increases diabetes susceptibility in females.