六溴环十二烷（HBCD)诱发肥胖的毒性效应及其分子机制研究

Hexabromocyclododecane (HBCD) is a high bromine content fire retardant, which belongs to the Persistent Organic Pollutants(POPs). HBCD is widely used in exterior building insulation materials, such as expanded polystyrene (EPS) and extruded polystyrene (XPS), and is also added into electrical equipment, high impact polystyrene (HIPS), and textile coatings. HBCD is prone to accumulate in the organism and adipose tissue is one of main organs which accumulated. Although there has been a number of studies focused on the toxicity of HBCD, the toxicity of HBCD on adipose is little mentioned and the influence of HBCD on obesity development and adipocytes is still to be unclear. Our group observed that HBCD exposure lead to preadipocyte differentiation and adipose accumulation in vivo in the previous study, in addition, others reported that HBCD exposure aggravated HFD induced obisity. Based on these realization, we will carry out following work in this project: 1) To reveal the effects of low dose HBCD exposure on obesity development in vivo; 2)To examine the effects of HBCD exposure on white preadipocyte differentiation, transdifferentiation between mature white adipocyte and beige adipocyte and elucidate the molecular mechanisms underlying HBCD exposure mediated obesity development by analyzing transcription factors, key signal transduction pathways correlated to white preadipocyte differentiation and transdifferentiation between mature white adipocyte and beige adipocyte . 3) To elucidate different effects of α-HBCD，β-HBCD，γ-HBCD on HBCD induced obesity. Thus, this project will provide theoretical basis and scientific guidance for the environmental health risky of HBCD.

持久性有机污染物六溴环十二烷(HBCD)是一种高含溴量阻燃剂，广泛应用在与人们日常生活密切相关的涤纶织物、塑料、纤维和建筑物保温材料中，HBCD进入机体主要富集在脂肪组织。尽管目前针对HBCD的毒性已开展了大量研究，但有关HBCD对脂肪组织的毒性却很少关注，HBCD对肥胖发生和脂肪细胞的影响仍不清楚。申请人前期的研究结果表明， HBCD暴露具有诱发腹内脂肪增加和干扰脂肪细胞分化的效应，此外，有文献报道HBCD具有加剧已有肥胖的效应。在此基础上，本项目将深入探讨：1）低剂量HBCD长期暴露诱发肥胖发生的毒性效应特征；2）HBCD暴露对白色脂肪细胞分化成熟、米色脂肪细胞与白色脂肪细胞转化的影响及相关转录因子、重要信号通路所介导的诱发肥胖的毒性机制研究；3）阐明α-HBCD，β-HBCD，γ-HBCD在促肥胖效应中的毒性效应差异。本项目的开展将为全面深刻评价HBCD的环境健康风险提供科学依据

持久性有机污染物六溴环十二烷(HBCD)是一种高含溴量阻燃剂，广泛应用在与人们日常生活密切相关的涤纶织物、塑料、纤维和建筑物保温材料中，HBCD进入机体主要富集在脂肪组织。尽管目前针对HBCD的毒性已开展了大量研究，但有关HBCD对脂肪组织的毒性却很少关注，HBCD对肥胖发生和脂肪细胞的影响仍不清楚。本课题主要开展环境相关剂量HBCD长期暴露诱发肥胖及其相关代谢紊乱的毒理学效应及机制研究。主要研究结果如下：1）环境相关剂量HBCD长期暴露会引起性别差异的促肥胖和代谢紊乱效应。HBCD长期暴露引起雄性小鼠体重增加、内脏白色脂肪含量增加，同时显著诱发肝脏甘油三酯含量增加及胰岛素抵抗；与之相反，HBCD暴露并不会影响雌性小鼠的体重及脂肪组织含量，非常有意思的是HBCD长期暴露会增强雌鼠的胰岛素敏感性。2）研究发现HBCD具有促进脂肪细胞分化的作用，HBCD的三种主要构型α-HBCD，β-HBCD，γ-HBCD促脂肪细胞分化效应具有构象依赖性，其中α-HBCD促脂肪细胞分化效应最显著。分子机制研究表明HBCD主要通过下调前脂肪细胞分化早期阶段（0～2天）Wnt6表达、抑制Wnt/β-catenin通路活化，进而促进下游脂肪细胞分化的关键调控因子PPARγ表达发挥促脂肪细胞分化的效应，进一步的体内实验研究表明促进前脂肪细胞分化与HBCD暴露雄鼠引起的腹内白色脂肪含量增加密切相关。3）研究发现HBCD暴露显著抑制雄鼠的能量消耗，对体内肩胛褐色脂肪、皮下白色脂肪及腹内白色脂肪分析表明HBCD暴露能够通过组织特异的方式不同程度的抑制褐色脂肪细胞及米色脂肪细胞能量消耗相关的产热功能，提示HBCD能够通过干扰褐色、米色脂肪的能量消耗促进肥胖及相关的糖脂代谢紊乱。综上所述，本课题的研究结果表明环境相关剂量的HBCD暴露会引起性别差异的促肥胖和代谢紊乱效应，进一步的机制研究表明HBCD通过促进白色脂肪细胞分化及抑制褐色、米色脂肪产热诱发肥胖及代谢紊乱。以上研究结果为理解HBCD的毒理学效应和机制提供了全新的内容，为全面评价HBCD的环境健康风险提供了非常有力的科学依据。