Low-dose dioxin exposure during pregnancy and lactation increases susceptibility to diet-induced diabetes in dams

Aim/hypothesis: Persistent 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. 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 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. Results: Dioxin-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/interpretations: Our study suggests that chronic low-dose dioxin exposure during pregnancy may contribute to the rapid rise in obesity and diabetes incidence seen worldwide.