2,3,7,8-四氯二苯并二噁英染毒或联合高脂饮食致小鼠糖脂代谢紊乱的实验研究

目的：探讨持久性有机污染物2，3，7，8-四氯二苯并二噁英（TCDD）染毒或联合高脂饮食对小鼠糖脂代谢的影响及其作用机制。方法：60只C57BL/6J小鼠随机分为4组，即对照组、高脂饮食组、TCDD染毒组、高脂饮食和TCDD染毒联合作用组，每组6只。高脂饮食采用脂肪热量为45%的高脂饲料，TCDD染毒按1 mg/（kg·d）采用饮水摄入方式。3周后测定小鼠体质量、脂肪质量、血糖、糖耐量、胰岛素耐量等指标评价糖脂代谢功能；特异性染色法测定线粒体膜电位和ROS水平，实时荧光定量PCR测定脂肪组织中抗氧化转录因子Nrf2、抗氧化酶（GCLc、GPx1和SOD2）和炎症因子（IL-1α、IL-6和MCP-1）的mRNA表达水平。结果：与对照组相比，TCDD染毒或高脂饮食均可诱导小鼠发生明显的糖脂代谢紊乱，主要表现为脂肪组织含量增加、血糖水平的升高和糖耐量、胰岛素耐量受损（P均<0.05）。TCDD可以加重高脂饮食对糖脂代谢的影响。在肝组织和脂肪组织，TCDD染毒或与高脂饮食联合均诱导线粒体超极化和ROS水平增加（P均<0.05），且TCDD可以加重高脂饮食对线粒体和ROS的影响（P均<0.05）。TCDD可降低Nrf2、GCLc和SOD2的表达，TCDD和高脂饮食联合作用，降低Nrf2及关键抗氧化酶的作用更为显著。TCDD使脂肪组织IL-1α、IL-6和MCP-1的表达显著升高，并加重高脂饮食对IL-1α、IL-6和MCP-1表达的影响（P均<0.05）。结论：TCDD染毒和高脂饮食对小鼠糖脂代谢指标、氧化应激指标、炎症因子表达的影响具有协同作用；TCDD和高脂饮食联合作用导致小鼠糖脂代谢功能紊乱的机制，可能为下调Nrf2及其调控的抗氧化酶并促进炎症因子表达。

2,3,7,8-tetrachlorodibenzo-p-dioxin alone or in combination with high fat diet on glucose and lipid metabolism in mice

OBJECTIVE:To investigate the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alone or in combination with high fat diet (HFD) on glucose and lipid metabolism in mice.METHODS:60 C57BL/6J mice were randomly divided into 4 control and treatment groups.All mice were evaluated for glucose and lipid metabolic functions through measurement of body weight,weights of liver and adipose tissues,glucose tolerance,and insulin tolerance,determined mitochondrial membrane potential and ROS level using specific probes,and measured the mRNA expression of Nrf2,antioxidant enzymes and inflammatory factors.RESULTS:TCDD or HFD alone could induce significant glucose and lipid metabolic disorders,as evidenced by increased adipose weight,increased blood glucose level,impaired tolerance of glucose and insulin.In addition,TCDD aggravated HFD-induced impairment of glucose and lipid metabolism.In liver,TCDD or HFD alone resulted in hyperpolarization of mitochondrial membrane potential and increased levels of ROS.TCDD and HFD induced a more significant mitochondrial dysfunction and increase in ROS.In adipose tissues,TCDD alone or in combination with HFD increased ROS level and perturbed HFD-induced ROS increase.In addition,TCDD decreased the mRNA expression of Nrf2,GCLc,and SOD2.In combination with HFD,the effect of TCDD on the mRNA expression of Nrf2,GCLc,and SOD2 was significantly enhanced.Either TCDD or HFD increased the mRNA expression of IL-1α,IL-6,and MCP-1.TCDD aggravated the HFD-induced increase of these inflammatory factors.CONSLUSION:TCDD and HFD induced glucose and lipid metabolic disorders in mice.In addition,they functioned cooperatively to affect glucose metabolic parameters,oxidative stress indexes,and expression of inflammatory factors In fact,the effects of TCDD in combination with HFD were stronger than the additive effects from each acting alone.The decrease of Nrf2,the downstream effects on antioxidant enzymes and the increase of inflammatory factors may be a key mechanism responsible for the observed cooperative effects.