Abstract
Objective Exposure to persistent organic pollutants is consistently associated with increased diabetes risk in humans. We investigated the short- and long-term impact of chronic low-dose dioxin (aka 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 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 on chow diet 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 also had accelerated onset of hyperglycemia, dysregulated insulin secretion, reduced islet size, increased MAFA- beta cells, and increased proinsulin accumulation following HFD feeding compared to control dams.
Conclusions Our mouse model suggests that chronic low-dose dioxin exposure may be a contributing factor to obesity and diabetes pathogenesis in females.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
RNAseq data from a separate but related cohort of non-pregnant female mice has been added to this paper to support histological findings in our pregnant mice.
Abbreviations
- AhR
- Aryl hydrocarbon receptor
- CO
- Corn Oil
- Cyp
- Cytochrome P450
- Cyp1a1
- Cytochrome P450 1A1
- Cyp1a2
- Cytochrome P450 1A2
- GDM
- Gestational diabetes mellitus
- GSIS
- Glucose stimulated insulin secretion
- GTT
- Glucose tolerance test
- HFD
- High fat diet
- ITT
- Insulin tolerance test
- POPs
- Persistent Organic Pollutants
- TCDD
- 2,3,7,8-tetrachlorodibenzo-p-dioxin