Perfluorooctanoic acid (PFOA) affects distinct molecular signalling pathways in human primary hepatocytes

Buhrke, T.; Krüger, E.; Pevny, S.; Rössler, M.; Bitter, K.; Lampen, A.

Perfluorooctanoic acid (PFOA) was shown to damage the liver of rodents and to impair embryonic development. At the molecular level, the hepatotoxic effects were attributed to the PFOA-mediated activation of peroxisome proliferator-activated receptor alpha (PPAR alpha). In general, PPAR alpha-dependent effects are less pronounced in humans than in rodents, and the hazard potential of PFOA for humans is controversially discussed. To analyse the effects of PFOA in human hepatocytes, a microarray analysis was conducted to screen for PFOA-mediated alterations in the transcriptome of human primary hepatocytes. A subsequent network analysis revealed that PFOA had an impact on several signalling pathways in addition to the well-known activation of PPARa. The microarray data confirmed earlier findings that PFOA: (i) affects the estrogen receptor ER alpha, (ii) activates the peroxisome proliferator-activated receptor gamma (PPAR gamma), and (iii) inhibits the function of the hepatocyte nuclear factor 4 alpha (HNF4 alpha) which is an essential factor for liver development and embryogenesis. Finally, as a novel finding, PFOA was shown to stimulate gene expression of the proto-oncogenes c-Jun and c-Fos. This was confirmed by using the HepG2 cell line as a model for human hepatocytes. PFOA stimulated cellular proliferation and the metabolic activity of the cells, and upregulated the expression of various cyclins which have a central function in the regulation of cell cycle control. Functional studies, however, indicated that PFOA had no impact on c-Jun and c-Fos phosphorylation and on AP-1-dependent gene transcription, thus demonstrating that PFOA-induced proliferation occurs largely independent of c-Jun and c-Fos.


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Buhrke, T. / Krüger, E. / Pevny, S. / et al: Perfluorooctanoic acid (PFOA) affects distinct molecular signalling pathways in human primary hepatocytes. 2015.


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