Perfluorooctanoic acid (PFOA) affects distinct molecular signalling pathways in human primary hepatocytes. (3rd July 2015)

• Record Type: Journal Article
• Authors: Buhrke, Thorsten; Krüger, Eileen; Pevny, Sophie; Rößler, Manuela; Bitter, Katja; Lampen, Alfonso
• Is Part Of: Toxicology. Volume 333(2015)
• Page Start: 53
• Page End: 62
• Publication Date: 2015-07-03
• Subjects: PFOA -- Hepatocyte -- Transcriptomics -- Cell cycle regulation; PFOA perfluorooctanoic acid -- c-Jun jun proto-oncogene -- c-Fos FBJ murine osteosarcoma viral oncogene homolog -- AP-1 activating protein 1; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.04.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Abstract: 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 (PPARα). In general, PPARα-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 PPARα. The microarray data confirmed earlier findings that PFOA: (i) affects the estrogen receptor ERα, (ii) activates the peroxisome proliferator-activated receptor gamma (PPARγ), and (iii) inhibits the function of the hepatocyte nuclear factor 4α (HNF4α) 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.