Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

Abstract

Exposure to environmental pollutants is consistently associated with increased diabetes risk in humans. In male mice, acute dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) exposure supresses insulin secretion. This study investigated the long-term effects of a single TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female mice. TCDD-exposed males displayed modest fasting hypoglycemia for ~4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, and decreased beta cell area. TCDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or beta cell area in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can supress basal insulin levels long-term in both sexes, but effects on metabolism are sex-dependent.

Female mice exposed to low-doses of dioxin during pregnancy and lactation have increased susceptibility to diet-induced obesity and diabetes

“…Our study shows that dioxins reach the pancreas and induce Cyp1a1 expression during pregnancy. However, unlike previous studies in non-pregnant mice [8,18], the degree of Cyp1a1 induction in the pancreas was much higher than in the liver mid-pregnancy. It is unclear whether pregnancy promotes greater dioxin accumulation in the pancreas compared to other tissues or if the pancreas may be more sensitive to AhR-mediated dioxin signaling mid-pregnancy.…”

“…TCDD-exposed males also displayed modest fasting hypoglycemia for ~4 weeks post-injection, increased insulin sensitivity, decreased beta cell area, and increased delta cell area. In contrast, TCDD-exposed females became transiently glucose intolerant 4 weeks after the single high-dose TCDD injection [18]. These results suggest that pollutants may increase diabetes risk by altering beta cell function and/or islet composition in a sex-dependent manner.…”

“…Human studies consistently report a positive association between serum concentrations of dioxin/dioxin-like chemicals with insulin-resistance [9][10][11] and increased diabetes incidence [12][13][14][15][16][17]. There is also growing evidence suggesting that POPs may impair beta cell function [8,[18][19][20][21]. In fact, our lab has shown that direct exposure of mouse and human islets to the highly persistent dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48-hours ex vivo led to a significant reduction in glucose-induced insulin secretion [8].…”

“…In fact, our lab has shown that direct exposure of mouse and human islets to the highly persistent dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for 48-hours ex vivo led to a significant reduction in glucose-induced insulin secretion [8]. In addition, a single high-dose injection of TCDD (20 µg/kg) in vivo reduced plasma insulin levels for up to 6 weeks in male and female mice [18]. TCDD-exposed males also displayed modest fasting hypoglycemia for ~4 weeks post-injection, increased insulin sensitivity, decreased beta cell area, and increased delta cell area.…”

Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases

“…Eventually, the hyperactivity of β-cells and high levels of blood glucose and lipids contributing to glucotoxicity and lipotoxicity, can stimulate β-cell apoptosis and further propagate the pathogenesis of T2D (Deng et al, 2010). In addition to the genetic component, T2D is also largely influenced by environmental stressors, such as prolonged physical inactivity and an unhealthy diet (i.e., fatty foods high in dioxins) (Hoyeck et al, 2020;Ibrahim et al, 2020), which FIGURE 5 | Epigenetic changes of pancreas in metabolic disease and dietary intervention. In metabolic disease (i.e., T2D), the initial proliferation of pancreatic β-cells increase insulin secretion, but eventual β-cell failure leads to hypoinsulinemia and hyperglycemia.…”