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

被引:68
作者
Buhrke, Thorsten [1 ]
Krueger, Eileen [1 ]
Pevny, Sophie [1 ]
Roessler, Manuela [1 ]
Bitter, Katja [1 ]
Lampen, Alfonso [1 ]
机构
[1] Fed Inst Risk Assessment, Dept Food Safety, D-10589 Berlin, Germany
关键词
PFOA; Hepatocyte; Transcriptomics; Cell cycle regulation; ACTIVATION; ALPHA; LIVER; PROLIFERATION; MOUSE; WATER; AP-1; LIFE;
D O I
10.1016/j.tox.2015.04.004
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:53 / 62
页数:10
相关论文
共 28 条
[1]   Estrogen-Like Activity of Perfluoroalkyl Acids In Vivo and Interaction with Human and Rainbow Trout Estrogen Receptors In Vitro [J].
Benninghoff, Abby D. ;
Bisson, William H. ;
Koch, Daniel C. ;
Ehresman, David J. ;
Kolluri, Siva K. ;
William, David E. .
TOXICOLOGICAL SCIENCES, 2011, 120 (01) :42-58
[2]   Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats [J].
Biegel, LB ;
Hurtt, ME ;
Frame, SR ;
O'Connor, JC ;
Cook, JC .
TOXICOLOGICAL SCIENCES, 2001, 60 (01) :44-55
[3]   Structure-Activity Relationships and Human Relevance for Perfluoroalkyl Acid-Induced Transcriptional Activation of Peroxisome Proliferation in Liver Cell Cultures [J].
Bjork, James A. ;
Wallace, Kendall B. .
TOXICOLOGICAL SCIENCES, 2009, 111 (01) :89-99
[4]   In vitro toxicological characterization of perfluorinated carboxylic acids with different carbon chain lengths [J].
Buhrke, Thorsten ;
Kibellus, Anja ;
Lampen, Alfonso .
TOXICOLOGY LETTERS, 2013, 218 (02) :97-104
[5]   Is Indirect Exposure a Significant Contributor to the Burden of Perfluorinated Acids Observed in Humans? [J].
D'eon, Jessica C. ;
Mabury, Scott A. .
ENVIRONMENTAL SCIENCE & TECHNOLOGY, 2011, 45 (19) :7974-7984
[6]   Embryotoxic effects of the marine biotoxin okadaic acid on murine embryonic stem cells [J].
Ehlers, Anke ;
Stempin, Sandra ;
Al-Hamwi, Regina ;
Lampen, Alfonso .
TOXICON, 2010, 55 (04) :855-863
[7]   Liver regeneration and repair: Hepatocytes, progenitor cells, and stem cells [J].
Fausto, N .
HEPATOLOGY, 2004, 39 (06) :1477-1487
[8]   Perfluorinated compounds - Exposure assessment for the general population in western countries [J].
Fromme, Hermann ;
Tittlemier, Sheryl A. ;
Voelkel, Wolfgang ;
Wilhelm, Michael ;
Twardella, Dorothee .
INTERNATIONAL JOURNAL OF HYGIENE AND ENVIRONMENTAL HEALTH, 2009, 212 (03) :239-270
[9]   A protocol for combined Photinus and Renilla luciferase quantification compatible with protein assays [J].
Hampf, Mathias ;
Gossen, Manfred .
ANALYTICAL BIOCHEMISTRY, 2006, 356 (01) :94-99
[10]   The toxicology of perfluorooctanoate [J].
Kennedy, GL ;
Butenhoff, JL ;
Olsen, GW ;
O'Connor, JC ;
Seacat, AM ;
Perkins, RG ;
Biegel, LB ;
Murphy, SR ;
Farrar, DG .
CRITICAL REVIEWS IN TOXICOLOGY, 2004, 34 (04) :351-384