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

By Geronimo Matteo, Myriam P Hoyeck, Hannah L Blair, Julia Zebarth, Kayleigh RC Rick, Andrew Williams, Remi Gagne, Julie K Buick, Carole Yauk, Jennifer E Bruin

Posted 13 Sep 2020
bioRxiv DOI: 10.1101/2020.09.12.294587

Objective: Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka dioxin), and increased diabetes risk, but rarely consider potential sex differences. We previously showed that a single high-dose TCDD exposure (20 ug/kg) decreased plasma insulin levels in both male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. The purpose of the current study was to determine whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in either chow-fed or high fat diet (HFD)-fed mice. Methods: Male and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females at 12 weeks for Tempo-Seq analysis. Results: Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. TCDD caused a modest increase in islet area in males irrespective of diet, but reduced % beta cell area within islets in females. RNAseq analysis of female islets also revealed abnormal changes to endocrine and metabolic pathways in TCDD-exposed HFD-fed females compared chow-fed females. Conclusions: Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.

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