Molecular mechanisms of the toxicity of perfluorooctanoic acid (PFOA)

• Applicants: Dr. Thorsten Buhrke; Professor Dr. Alfonso Lampen
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 252059868

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.

• DFG Programme: Research Grants