溴系阻燃剂TBBPA致血管发育损伤及基于糖代谢紊乱的毒性机制研究

Tetrabromobisphenol A, (TBBPA) is the largest brominated flame retardant in the world and extensively existing in the environment. Given that previous studies mainly focused on the general developmental toxicity, endocrine disruption and neurotoxicity, the effects on the vascular development, which transport the nutrient substance and support for the development process and the growth of other organs, are largely unknown. Glycometabolism is the main energy source of vascular development. This project is to investigate the effects of TBBPA on the vasculature throughout the body based on the Tg(kdrl:eGFP) transgenic zebrafish. The impacts of TBBPA on the vascular cell differentiation and proliferation will be revealed using Tg(kdrl:eGFP) transgenic zebrafish and iPSC-EC cell model. Isotopic tracer metabolic flux analysis will be applied to characterize the key metabolic pathway, enzymes and metabolites of glycometabolism. The inhibitor or agonist of the target metabolic pathways and enzymes will be applied to in vitro and in vivo studies to elucidate the molecular mechanism of vascular developmental toxicity. Based on these studies, the key molecular event, action of model and signaling pathway of TBBPA exposure will be characterized，which will provide valuable insights into the elucidation of vascular developmental toxicity, screening of biomarkers and biological monitoring of TBBPA.

四溴双酚A（tetrabromobisphenol A，TBBPA）是目前全球用量最大的溴系阻燃剂，环境负荷逐渐加重。发育毒性是其主要毒性效应，但对为发育过程提供营养的血管的影响知之甚少。糖代谢是血管发育过程中的主要供能来源。本研究拟采用血管特异性标记斑马鱼观察TBBPA暴露对分布全身血管系统发育的影响，分析TBBPA对不同血管的发育毒性，筛选敏感靶标。结合斑马鱼和iPSC-EC细胞模型，从整体和细胞水平探讨TBBPA暴露对血管发育过程中血管细胞的分化和增殖的影响。利用同位素示踪代谢流组学深入探讨TBBPA对血管发育过程中糖代谢途径、代谢酶和代谢产物的变化。采用关键糖代谢途径激活剂或抑制剂观察其对血管发育毒性的拮抗或协同效应，确认关键分子事件、毒作用模式、毒作用靶点和毒性通路，阐明糖代谢紊乱在TBBPA致血管发育毒性中的调控机制，为TBBPA敏感生物标志物的筛选及早期生物监测提供关键依据。

四溴双酚A（tetrabromobisphenol A，TBBPA）是环境中广泛存在的持久性有机污染物，发育毒性是其主要毒性效应，但对为发育过程提供营养的血管发育的影响知之甚少。糖代谢是血管发育过程中的主要供能来源。主要研究内容采用血管特异性标记斑马鱼观察TBBPA暴露对分布全身的血管系统发育的影响，分析TBBPA对不同血管的发育毒性，筛选敏感靶标。结合斑马鱼和内皮细胞模型，从整体和细胞水平探讨TBBPA暴露对血管发育过程中血管细胞的分化和增殖的影响，确认易感阶段。利用代谢组学深入探讨TBBPA对血管发育过程中糖代谢途径、代谢酶和代谢产物的变化。采用关键糖代谢途径激活剂或抑制剂观察其对血管发育毒性的拮抗或协同效应，确认关键分子事件、毒作用模式、毒作用靶点和毒性通路，阐明糖代谢紊乱在TBBPA致血管发育毒性中调控机制。研究发现TBBPA暴露在不引起一般发育毒性指标改变的情况下，抑制血管发育，主要影响体节间血管、总主静脉、背主动脉及后主静脉的发育，其中对早期形成的背主动脉影响最为明显，说明DA为TBBPA暴露的敏感靶点和易感阶段。同时发现低剂量TBBPA暴露扰动线粒体氧化磷酸化及糖酵解途径，线粒体氧化磷酸化、三羧酸循环、脂肪酸为TBBPA暴露致血管内皮损伤的关键通路，为阐明 TBBPA 的血管发育毒性机制、生物标志物筛选和风险评估提供重要依据。