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

Myriam P Hoyeck,Mariam Elsawy,Hannah Blair,Shivani Solanki,Arina Prakash,Geronimo Matteo,Kayleigh R C Rick,Muna Ibrahim,Jennifer E Bruin,Shannon O’Dwyer

doi:10.1038/s41598-020-57973-0

Myriam P Hoyeck, Mariam Elsawy + Show 8 more

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https://doi.org/10.1038/s41598-020-57973-0

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Abstract

Epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans. We have previously shown that direct exposure of mouse and human islets (endocrine pancreas) to the highly persistent pollutant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes reduced insulin secretion ex vivo. Furthermore, a single high-dose of TCDD (200 µg/kg) suppressed both fasting and glucose-induced plasma insulin levels and promoted beta-cell apoptosis after 7 days in male mice. The current study investigated the longer-term effects of a single high-dose TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female C57Bl/6 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, decreased beta cell area, and increased delta 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 islet composition in females, but did cause transient glucose intolerance 4 weeks post-exposure. Our results show that a single exposure to dioxin can suppress basal insulin levels long-term in both sexes, but effects on glucose homeostasis are sex-dependent.

Highlights

Epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans
Dioxins and dioxin-like compounds are a broad class of persistent organic pollutants (POPs) that activate the aryl hydrocarbon receptor (AhR), which induces a variety of target genes, including cytochrome P450 (Cyp)1a1 and Cyp1a2
During a glucose tolerance test (GTT) at 2 weeks post-injection, mice exposed to 200 μg/kg TCDD showed severe hypoglycemia (Fig. 1D) and a dramatic decrease in plasma insulin levels (Fig. 1E)

Summary

Introduction

Epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans. The current study investigated the longer-term effects of a single high-dose TCDD injection (20 μg/kg) on glucose metabolism and beta cell function in male and female C57Bl/6 mice. We observed a substantial increase in beta cell apoptosis in these mice, suggesting that TCDD affects both beta cell function and survival[7] This high dose of TCDD caused significant weight loss and severe hypoglycemia after 2 weeks, which prevented us from assessing longer-term metabolic effects of transient TCDD exposure in vivo. Another limitation of our previous study was that we only examined male mice, similar to other groups[18,20,21,22]. The purpose of this study was to investigate the long-term implications of a single exposure to TCDD on glucose homeostasis and islet cell physiology in male and female mice, using a lower dose than in our previous work

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