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.

中文翻译：

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长时间低剂量二恶英暴露会损害雌性小鼠而非高脂小鼠对高脂饮食喂养的代谢适应性

目的：人体研究始终显示，暴露于持久性有机污染物（包括2,3,7,8-四氯二苯并-对二恶英（TCDD，又名二恶英））与糖尿病风险增加之间存在关联，但很少考虑潜在的性别差异。我们先前显示，一次高剂量TCDD暴露（20 ug / kg）会降低体内雄性和雌性小鼠的血浆胰岛素水平，但对葡萄糖稳态的影响是性别依赖性的。本研究的目的是确定长期摄入低剂量的TCDD在生理上相关是否会以性别依赖的方式影响食物的葡萄糖稳态和/或胰岛表型，无论是高脂饮食还是高脂饮食（HFD）喂养老鼠。方法：雄性和雌性小鼠每周两次接受20 ng / kg / d TCDD 2x暴露，持续12周，同时喂养标准食物或45％HFD。通过葡萄糖和胰岛素耐受性测试评估葡萄糖稳态，并在体内测量葡萄糖诱导的血浆胰岛素水平。对雄性和雌性小鼠的胰腺进行组织学分析，并在12周时从雌性中分离出胰岛进行Tempo-Seq分析。结果：低剂量的TCDD暴露不会对以粗饲料喂养的雄性或雌性小鼠或以HFD喂养的雄性小鼠产生不利的代谢后果。然而，TCDD加快了雌性小鼠中HFD引起的高血糖症的发作，并损害了葡萄糖诱导的血浆胰岛素水平。TCDD导致男性的胰岛面积适度增加，而与饮食无关，但女性的胰岛内β细胞百分比减少。雌性胰岛的RNAseq分析还显示，与以普通食物喂养的雌性相比，暴露于TCDD的HFD喂养的雌性的内分泌和代谢途径发生异常变化。结论：