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

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-tetrachlorodibenzop-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 longterm in both sexes, but effects on glucose homeostasis are sex-dependent. Diabetes mellitus is one of the leading causes of death worldwide, and its prevalence is increasing at alarming rates 1. Type 2 diabetes (T2D) is the most common form of diabetes, and is characterized by chronic hyperglycemia, peripheral insulin resistance, and insufficient insulin production by pancreatic beta cells 2. The rapid increase in diabetes incidence worldwide cannot be accounted for by genetics and lifestyle alone, suggesting that other environmental factors are likely contributing to diabetes etiology. In particular, epidemiological studies have reported an association between exposure to persistent organic pollutants (POPs) and increased diabetes incidence 3,4. However, while epidemiological studies can uncover correlative associations, basic research in model systems is required to investigate causation. Generally, POPs are lipophilic chemicals that resist degradation, leading to widespread global dispersion, bioaccumulation, and long-term release into the environment 5. Dioxins and dioxin-like compounds are a broad class of POPs that activate the aryl hydrocarbon receptor (AhR), which induces a variety of target genes, including cytochrome P450 (Cyp)1a1 and Cyp1a2. Although CYP enzymes are essential for xenobiotic metabolism, CYP-mediated substrate oxidation can also generate highly reactive intermediate metabolites that cause oxidative stress and DNA/protein damage 6. Our lab has shown that CYP1A enzymes are inducible and functional in human and mouse pancreatic islets, and that these enzymes remain active for at least two weeks following a single acute exposure to the classic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 7. These data indic...

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

“…We previously showed that CYP1A1 is induced and functional in human and mouse pancreatic islets following exposure to the highly persistent dioxin 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD, also referred to as dioxin) in vitro [ 8 ]. Cyp1a1 was also upregulated in mouse islets after systemic TCDD administration in vivo [ 8 , 9 ], indicating that dioxins reach the endocrine pancreas, which may impact beta cell function and survival. Indeed, TCDD-exposed mouse and human islets had significantly reduced glucose-induced insulin secretion in vitro [ 8 ], and a single high-dose injection of TCDD (20 μg/kg) reduced plasma insulin levels for up to 6 weeks in male and female mice in vivo [ 9 ].…”

Human Pluripotent Stem Cells: A Unique Tool for Toxicity Testing in Pancreatic Progenitor and Endocrine Cells

“…Additionally, we and others have shown that dioxin suppresses insulin secretion in rodent islets ( 73 , 79 , 80 ) and human islets ( 73 ). Interestingly, acute high-dose dioxin exposure caused β-cell apoptosis in male mice but not female mice ( 81 ), whereas prolonged low-dose dioxin exposure led to impaired β-cell adaptation to high fat diet feeding in female but not male mice ( 74 , 82 ).…”

Is There a Role for Environmental and Metabolic Factors Predisposing to Severe COVID-19?

“…Acute dioxin exposure led to long-term metabolic consequences in mice [59]. Organochlorine pesticides may potentially mediate insulin resistance [60].…”