Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada.
Department of Neuroscience, Carleton University, Ottawa, ON, Canada.
Mol Metab. 2020 Dec;42:101104. doi: 10.1016/j.molmet.2020.101104. Epub 2020 Oct 16.
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.
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.
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 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.
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.
接触持久性有机污染物与人类患糖尿病的风险增加密切相关。我们研究了孕期和哺乳期短暂低剂量二恶英（2,3,7,8-四氯二苯并对二恶英，TCDD）暴露对雌性小鼠葡萄糖稳态和β细胞功能的短期和长期影响，包括它们对生命后期代谢应激的反应。
雌性小鼠在交配、怀孕和哺乳期内每周接受 2 次 20ng/kg/d TCDD 或玉米油（CO；载体对照）注射，然后在化学暴露停止后再追踪 6-10 周。一部分 CO 和 TCDD 暴露的母鼠随后被转移到 45%高脂肪饮食（HFD）或继续标准的chow 饮食 11 周，以评估 TCDD 对代谢应激适应能力的长期影响。总之，雌性小鼠短暂暴露于 TCDD，然后在 TCDD 排出后进行追踪，以确定 TCDD 暴露对代谢影响的持久性。
TCDD 暴露的母鼠在出生时血糖水平较低，但在 TCDD 暴露期间和之后，葡萄糖稳态正常。然而，在接受 TCDD 注射后的第 5 周，开始食用 chow 饮食的 TCDD 暴露母鼠比对照组略重，并且在转换为 HFD 后体重增加加速。与对照组相比，TCDD 暴露的母鼠在 HFD 喂养后也出现了血糖升高加速、葡萄糖诱导的血浆胰岛素水平降低、胰岛体积减小、MAFAβ细胞增加和前胰岛素积累增加。总的来说，我们的研究表明，孕期低剂量 TCDD 暴露对活跃暴露期间的代谢影响较小，但对 HFD 喂养的代谢适应性有不利的长期影响。
我们的研究表明，雌性小鼠短暂低剂量 TCDD 暴露会损害对 HFD 喂养的代谢适应性，表明二恶英暴露可能是女性肥胖和糖尿病发病机制的一个促成因素。
