Objective Exposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of transient low-dose dioxin (2,3,7,8-tetrachlorodibenzo- p -dioxin, TCDD) exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life. Methods Female mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy and lactation, and then tracked for 6–10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams was then transferred to a 45% high-fat diet (HFD) or remained on a standard chow diet for an additional 11 weeks to assess the long-term effects of TCDD on adaptability to a metabolic stressor. To summarize, female mice were transiently exposed to TCDD and then subsequently tracked beyond when TCDD had been excreted to identify lasting metabolic effects of TCDD exposure. Results TCDD-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-TCDD exposure. However, TCDD-exposed dams on a chow diet were modestly heavier than controls starting 5 weeks after the last TCDD injection, and their weight gain accelerated after transitioning to a HFD. TCDD-exposed dams also had an accelerated onset of hyperglycemia, impaired glucose-induced plasma insulin levels, reduced islet size, increased MAFA -ve beta cells, and increased proinsulin accumulation following HFD feeding compared to controls. Overall, our study demonstrates that low-dose TCDD exposure during pregnancy has minimal effects on metabolism during the period of active exposure, but has detrimental long-term effects on metabolic adaptability to HFD feeding. Conclusions Our study suggests that transient low-dose TCDD exposure in female mice impairs metabolic adaptability to HFD feeding, demonstrating that dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.

Melanin‐concentrating hormone (MCH) neurons within the hypothalamus are heterogeneous and can coexpress additional neuropeptides and transmitters. The majority of MCH neurons express vesicular transporters to package glutamate for synaptic release, and MCH neurons can directly innervate downstream neurons via glutamate release. Although glutamatergic signalling from MCH neurons may support physiological and behavioural roles that are independent of MCH (e.g., in glucose homeostasis and nutrient‐sensing), it can also mediate similar roles to MCH in the regulation of energy balance. In addition to energy balance, the MCH system has also been implicated in mood disorders, as MCH receptor antagonists have anxiolytic and anti‐depressive effects. However, the contribution of glutamatergic signalling from MCH neurons to mood‐related functions have not been investigated. We crossed Mch‐cre mice with floxed‐Vglut2 mice to delete the expression of the vesicular glutamate transporter 2 (Vglut2) and disable glutamatergic signalling specifically from MCH neurons. The resulting Mch‐Vglut2‐KO mice showed Vglut2 deletion from over 75% of MCH neurons, and although we did not observe changes in depressive‐like behaviours, we found that Mch‐Vglut2‐KO mice displayed anxiety‐like behaviours. Mch‐Vglut2‐KO mice showed reduced exploratory activity when placed in a new cage and were quicker to consume food placed in the centre of a novel open arena. These findings showed that Vglut2 deletion from MCH neurons resulted in anxiolytic actions and suggested that the anxiogenic effects of glutamate are similar to those of the MCH peptide. Taken together, these findings suggest that glutamate and MCH may synergize to regulate and promote anxiety‐like behaviour.

AbstractAim/hypothesisPersistent organic pollutants have consistently been associated with increased diabetes risk in humans. However, very few studies have assessed the risk of chronic low-dose exposure to pollutants during pregnancy. We investigated the short- and long-term impact of chronic low-dose dioxin exposure during pregnancy and lactation on glucose homeostasis and beta cell function in female mice, including their response to a metabolic stressor later in life.MethodsFemale mice were injected with either corn oil (CO; vehicle control) or 20 ng/kg/d TCDD 2x/week throughout mating, pregnancy, and lactation, and then tracked for 6-10 weeks after chemical exposure stopped. A subset of CO- and TCDD-exposed dams were then transferred to a 45% high fat diet (HFD) or remained on standard chow diet for an additional 11 weeks to assess long-term effects of TCDD on adaptability to a metabolic stressor.ResultsDioxin-exposed dams were hypoglycemic at birth but otherwise had normal glucose homeostasis during and post-dioxin exposure. However, dioxin-exposed dams were modestly heavier than controls starting 5 weeks after the last dioxin injection, and their weight gain accelerated after transitioning to a HFD. Dioxin-exposed dams fed HFD also had accelerated onset of hyperglycemia, dysregulated insulin secretion, reduced islet size, increased MAFA- beta cells, and impaired proinsulin processing compared to control dams on HFD.Conclusions/interpretationsOur study suggests that chronic low-dose dioxin exposure during pregnancy may contribute to the rapid rise in obesity and diabetes incidence seen worldwide.