全氟辛基磺酸（PFOS）和全氟辛基羧酸（PFOA）作为典型的全氟类化合物，可通过食物链传递放大并最终进入人体，对人类健康造成潜在危害。基于实验结果和文献分析，我们提出一个新的科学假设：PFOS/PFOA可通过干扰肝脏的糖异生，影响动物体内的糖/脂代谢平衡，最终造成受试动物肝脏肿大和脂肪组织萎缩。本项目将针对该科学假设，拟结合使用HepG2肝癌细胞株和BALB/c小鼠等离体、活体实验模型，通过测定不同浓度毒物暴露不同时间后，细胞和组织中葡萄糖、丙酮酸、乙酰辅酶A等主要中间代谢物的变化，定量检测细胞内糖异生、糖酵解、三羧酸循环等关键代谢途径中各限速酶的表达水平，建立剂量-效应曲线，以揭示PFOS/PFOA干扰肝脏糖/脂代谢的具体靶分子，再结合利用激素或受体抑制剂激活或阻断实验模型中特定代谢途径，深入研究并阐明PFOS/PFOA干扰肝细胞中糖异生和受试动物体内脂质代谢的作用途径和分子致毒机制。

As typical poly-and perfluorinated alkyl substances (PFASs), perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) can be bio-concentrated through the food chain and finally occur in human bodies, this might pose potential hazards to human health. In the previous studies, we have found that PFOS/PFOA exposure caused abnormal lipid accumulation in livers, atrophied adipose tissues and declined serum glucose level in rodents. Basing on those observations, we hypothesize that PFOS/PFOA may affect lipid and glucose homeostasis by disturbing gluconeogenesis in the liver, and finally this would result in enlarged livers and atrophied adipose tissues of the exposed animals. To test this hypothesis, cultured cells and animal model such as HepG2 cells and BALB/c mice will be used in this study. Following exposure to different doses of the toxicants for certain time, intermediate metabolites such as glucose, pyruvic acid and acetyl-CoA in HepG2 cells, as well as blood, liver and adipose tissues of animals will be measured. In addition, Expression of rate-limiting enzyme involved in the key metabolic pathways of gluconeogenesis, glycolysis and TCA cycle will be examined. Dose-effect curves will be established, aiming to reveal the target molecules of PFOS/PFOA-caused glucose/lipid metabolic disorders. Hormone or receptor antagonist will be used to activate or block certain metabolic pathways in these models. That will give an insight into how PFOS/PFOA affects the gluconeogenesis of HepG2 cells and lipid transportations in exposed animals. Furthermore, molecular mechanism will be explained for PFOS/PFOA-caused glucose/lipid metabolic disorders. Collectively, this study will provide scientific basis for PFOS/PFOA-caused health effects, as well as rationale for substitute products for PFOS.