Molecular mechanisms of the toxicity of perfluorooctanoic acid (PFOA)

全氟辛酸（PFOA）是一种工业化学品，用于制造许多具有拒油、拒污和拒水特性的产品。PFOA具有耐化学、耐热和生物降解的特性，已成为土壤、水、空气和食物的全球性污染物。PFOA的毒理学数据令人担忧，因为该物质被证明会损害啮齿动物的肝脏并损害胚胎发育。目前，人们对PFOA对人体的潜在危害存在争议。我们自己的初步研究表明，在分子水平上，PFOA影响人原代肝细胞的不同信号传导和代谢途径。具体来说，PFOA在人肝细胞中引起(1)过氧化物酶体增殖物激活受体α (ppar α)的激活，(2)肝细胞核因子4 α (hnf4 α)的抑制，以及(3)通过增强原癌基因c-Jun和c-Fos的表达来调节AP-1转录因子的活性。在动物模型中也观察到PFOA介导的pparα活化，而PFOA对转录因子HNF4alpha和AP-1的影响迄今尚未在这些动物模型中报道。因此，这些影响可能是人类特有的影响，这是本提案的重点。转录因子HNF4alpha在胚胎发生、肝脏发育以及脂质和能量代谢中具有中心功能。降低HNF4alpha活性可能促进糖尿病。本项目的重点是PFOA和HNF4alpha之间假设的直接相互作用的特征，以及PFOA对胰腺β细胞的假设损伤。在AP-1转录因子的情况下，c-Fos表达的增加与细胞增殖的增强相关。因此，我们将研究PFOA对细胞周期控制的影响。基于这一事实的活动AP-1复杂的监管不仅通过表达AP-1组件(如c-Fos也通过这些组件的磷酸化,PFOA在磷酸化级联的影响特征,最终目标假设膜受体的识别,提出了由全氟辛酸及其盐类(PFOA)作为细胞外配体刺激从而引发上述磷酸化级联。综上所述，这些研究结果将有助于在分子水平上了解PFOA在人肝细胞中的新作用模式。此外，它们将对PFOA的实际毒理学风险评估作出重大贡献。

Perfluorooctanoic acid (PFOA) is an industrial chemical that is used for the fabrication of numerous products with oil-, dirt- and water-repellent properties. PFOA is resistant to chemical, thermal and biological degradation and has become a global contaminant of soil, water, air and food in the meantime. The toxicological data of PFOA give cause for concern as the substance was shown to damage the liver of rodents and to impair embryo development. Currently, the hazard potential of PFOA for humans is controversially discussed. Our own preliminary studies revealed that on the molecular level PFOA affects different signalling and metabolic pathways in human primary hepatocytes. Concretely, PFOA caused in human liver cells (i) an activation of peroxisome proliferator-activated receptor alpha (PPARalpha), (ii) an inhibition of hepatocyte nuclear factor 4 alpha (HNF4alpha), and (iii) a modulation of the activity of the AP-1 transcription factor via an enhanced expression of the proto-oncogenes c-Jun and c-Fos. PFOA-mediated activation of PPARalpha has also been observed in the animal models whereas effects of PFOA on the transcription factors HNF4alpha and AP-1 have not been reported so far for these animal models. Therefore, these effects might be human-specific effects which are in the focus of this proposal. The transcription factor HNF4alpha has central functions in embryogenesis, liver development and in lipid and energy metabolism. Reduced HNF4alpha activity may promote diabetes. This project focuses on the characterisation of the postulated direct interaction between PFOA and HNF4alpha as well as on a putative impairment of pancreatic beta-cells by PFOA. In the case of the AP-1 transcription factor an increased expression of c-Fos correlates with an enhanced cellular proliferation. Therefore, the impact of PFOA on cell cycle control will be examined. Based on the fact that the activity of the AP-1 complex is regulated not only via the expression of the AP-1 components such as c-Fos but also via the phosphorylation of these components, the impact of PFOA on this phosphorylation cascade will be characterised, finally aiming on the identification of the postulated membrane receptor that is proposed to be stimulated by PFOA as an extracellular ligand thereby triggering the phosphorylation cascade mentioned above.Taken together, the results of these studies will contribute to the understanding of novel modes of action of PFOA in human liver cells on the molecular level. Moreover, they will substantially contribute to the actual toxicological risk assessment of PFOA.