title: Perfluorooctanoic acid (PFOA) affects distinct molecular signalling pathways in human primary hepatocytes.
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.
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: thorsten.buhrke@bfr.bund.de.
authors: Thorsten
authors: T
authors: Buhrke
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors: Eileen
authors: E
authors: Krüger
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors: Sophie
authors: S
authors: Pevny
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors: Manuela
authors: M
authors: Rößler
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors: Katja
authors: K
authors: Bitter
authors: Federal Institute for Risk Assessment, Department of Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors: Alfonso
authors: A
authors: Lampen
mesh_terms: D002210:Caprylates / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005466:Fluorocarbons / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002210:Caprylates; D016213:Cyclins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D005466:Fluorocarbons; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D047493:PPAR alpha; D047495:PPAR gamma; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C023036:perfluorooctanoic acid
keywords: Cell cycle regulation; Hepatocyte; PFOA; Transcriptomics