低剂量壬基酚暴露增加代谢综合征风险及机制研究

The incidence of Metabolic Syndrome (MS) is rising at epidemic rates over the last several decades. There is mounting evidence suggesting that the increased presence of environmental endocrine disrupting chemicals (EDDs) plays an important part in the prevalence of metabolic syndrome. Nonylphenol(NP)，an endocrine disrupting chemical with estrogenic activity, competes with estrogen for estrogen receptors in target organs to induce the interruption of internal hormone balance, which represents serious threat to the health of the population. Prior studies testified that sex hormone levels were associated with MS, however, whether exposure to NP would increase the risk of MS and its possible mechanism has not been elucidated. Our project plans to carry out an population investigation at first, which detects serum NP and sex hormone levels, and made a comparison in these indicators between the patients with metabolic syndrome and a group of healthy people; Secondly, our project intends to use an animal model to address the adverse effects of perinatal low-level NP exposure on glucose and lipid homeostasis as well as hepatocyte lipid metabolism in rat offspring, which used to clarify the relationship between NP exposure and an increase in risk of MS. Finally, we plan to perform molecular biology tests to detect the expression of genes involved in adipocyte differentiation, liver lipid metabolism and insulin secretion in pancreatic islets; an association between these indicators and changes in sex hormone levels and estrogen receptors in target organs in body will be observed to investigate the role and possible mechanism of induction of MS from the estrogen-like effects of NP at molecular level. Our project will be conducive to provide a theoretical basis for effective prevention strategies for MS (e.g., intervention and antagonism of androgen or Chinese medicine to the estrogen-like effects of NP ) and screen differentially expressed sensitive genes in target organs.

代谢综合征（MS）发病率急剧增高，环境内分泌干扰物暴露是其不可忽视的危险因素之一。壬基酚(NP)是具有拟雌激素样作用的环境内分泌干扰物，可与雌激素竞争靶器官上的雌激素受体（ER）来干扰体内激素平衡，影响机体健康。研究证实，性激素水平与MS关系密切，关于NP暴露是否增加MS发生的风险及可能机制，目前尚未见阐明。 本项目拟通过人群调查比较MS患者和健康人群体内NP含量和性激素水平的差异；通过动物实验观察围产期NP暴露对仔鼠脂质稳态、血糖稳态和肝细胞代谢的影响，阐明NP暴露与MS的关系；分析暴露组和对照组脂肪细胞分化、肝脏脂质代谢、胰岛分泌功能相关基因表达的差异, 从NP拟雌激素样作用→体内激素平衡破坏→靶器官ER表达变化→靶器官的功能及基因表达异常这几个环节，初步探讨NP的拟雌激素样作用在MS发病中作用机理。本课题可为为制定NP的环境最高容许浓度和MS防治策略提供实验依据。

代谢综合征（MS）发病率急剧增高，目前认为环境内分泌干扰物暴露是其不可忽视的危险因素之一。壬基酚(NP)是环境内分泌干扰物的典型代表，NP在工业生产中广泛应用，环境污染严重，对人类健康产生了极大威胁，目前关于环境浓度NP暴露是否会增加机体MS风险及其可能机制尚未见阐明。. 本项目通过动物实验和人群调查相结合，探讨NP暴露于MS发病关系，研究结果显示：①人群调查发现，人群体内NP含量平均值为559ng/ml，糖尿病组血糖、NP含量、雌激素受体浓度均高于健康组，且NP含量与血糖、ER、甘油三酯呈正相关，与高密度脂蛋白胆固醇呈负相关；②动物实验发现，慢性NP暴露后可在血清和胰腺组织中蓄积并发挥毒作用，NP可诱导大鼠糖耐量异常，引起胰岛素抵抗，造成胰岛β细胞功能障碍，诱发大鼠糖代谢紊乱。NP影响胰腺UCP-2、GK和GLUT-2等糖代谢关键基因和蛋白的表达水平，这可能是NP暴露导致糖代谢紊乱的初步机制之一。NP和高脂饲料联合暴露可增大糖尿病发病风险。③2 μg/kg NP可加重高脂高糖饮食致大鼠非酒精性脂肪肝效应，可能与上调Srebp1，Fas，Ucp2 mRNA表达，增强c/EBPα、PPARγ表达，增加TG合成有关。④高糖饮食联合NP慢性暴露可导致高血脂和肥胖，病理可见，随着NP染毒剂量的增加，脂肪细胞个数减少，单个细胞平均面积增大，可能和NP干扰脂肪细胞脂质代谢促进脂肪细胞肥大有关。⑤课题组改良了动物血清与组织中NP含量的检测方法，用弱酸做流动相，可将检测效率提高，与常规方法相比，更灵敏，回收率高；⑥采用地方特色食品对NP毒性进行干预，对比锌硒茶干预组、普通绿茶干预组和NP暴露组的体重、血糖、瘦素、脂肪系数、肝脏系数，胰腺、肝脏组织的细胞水肿、炎症、坏死等方面，发现锌硒茶1.20 g/kg/day对NP暴露致大鼠代谢综合征有一定保护作用，锌硒茶干预效果优于普通绿茶组。