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

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 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.

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

“…Furthermore, HFD feeding induced hyperinsulinemia in CO-exposed female mice and both TCDD-and CO-exposed male mice, but failed to induce compensatory hyperinsulinemia in TCDD-exposed females. These findings are in line with our previous work showing that female mice exposed to low-dose TCDD during pregnancy/lactation and subsequently fed HFD later in life had accelerated onset of hyperglycemia and transient low glucose-induced plasma insulin levels compared to COHFD females (22). Furthermore, RNA-Seq analysis on isolated islets revealed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females.…”

“…Further, the compensatory increase in Nkx6.1 in COHFD females compared to COChow was absent in TCDDHFD females. These findings are consistent with our pregnancy model showing a reduced proportion of beta cells expressing MAFA in the pancreas of TCDDHFD females compared to COHFD females (22). The beta cell transcription factors MAFA, PDX1, HNF4α, and PAX6 form an essential network for maintaining beta cell identity and regulating genes involved in insulin secretion (e.g.…”

“…COChow vs TCDDChow) and/or accelerate diet-induced obesity (i.e. COHFD vs TCDDHFD), as previously seen in female mice exposed to TCDD during pregnancy (22). Interestingly, TCDD exposure had no effect on body weight in chow-fed females in this study (Fig.…”

“…Furthermore, RNA-Seq analysis on isolated islets revealed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females. TCDD exposure alone did not impact glucose homeostasis or plasma insulin levels in either sex in this study or in the pregnancy model (22), suggesting that this persistent pollutant is more of a concern when combined with a secondary metabolic stressor.…”

“…Our in vivo results (Figs. 2-3) and previous findings from a separate study in pregnant mice (22) suggest that background exposure to TCDD accelerates HFD-induced changes in metabolism in female mice. As such, we next investigated the effects of HFD feeding on the islet transcriptome of females with either CO or TCDD background exposure (i.e.…”