Toxicogenomics directory of chemically exposed human hepatocytes
Artikel i vetenskaplig tidskrift, 2014
A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes.
In vivo validation
Steatosis
Toxicotranscriptomics
Hepatotoxicity
Cirrhosis
Bioinformatics
Biomarker identification
Unsupervised clustering
SEURAT-1
Hepatocellular cancer
Författare
Marianna Grinberg
Technische Universität Dortmund
Regina M. Stoeber
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
K. Edlund
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Eugen Rempel
Technische Universität Dortmund
Patricio Godoy
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Raymond Reif
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Agata Widera
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Katrin Madjar
Technische Universität Dortmund
Wolfgang Schmidt-Heck
Hans-Knoll-Institute (HKI)
Rosemarie Marchan
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Agapios Sachinidis
Universität zu Köln
Dimitry Spitkovsky
Universität zu Köln
Jurgen Hescheler
Universität zu Köln
Helena Carmo
Universidade do Porto
Marcelo D. Arbo
Universidade do Porto
Bob van de Water
Universiteit Leiden
Steven Wink
Universiteit Leiden
Mathieu Vinken
Vrije Universiteit Brüssel (VUB)
Vera Rogiers
Vrije Universiteit Brüssel (VUB)
Sylvia Escher
Fraunhofer Institut fur Toxikologie und Experimentelle Medizin - ITEM
Barry Hardy
Dragana Mitic
Cambridge Cell Networks Ltd
Glenn Myatt
Leadscope
Tanja Waldmann
Universität Konstanz
Adil Mardinoglu
Chalmers, Kemi- och bioteknik, Livsvetenskaper
Georg Damm
Charité Universitätsmedizin Berlin
Daniel Seehofer
Charité Universitätsmedizin Berlin
Andreas Nuessler
Universität Tübingen
Thomas S. Weiss
Universität Regensburg
Axel Oberemm
Bundesinstitut Fuer Risikobewertung
Alfons Lampen
Bundesinstitut Fuer Risikobewertung
Mirjam M. Schaap
Netherlands National Institute Public Health and the Environment
Mirjam Luijten
Netherlands National Institute Public Health and the Environment
Harry van Steeg
Netherlands National Institute Public Health and the Environment
Wolfgang E. Thasler
Klinikum der Universitat Munchen
Jos C. S. Kleinjans
Universiteit Maastricht
Rob H. Stierum
Nederlandse Organisatie voor toegepast-natuurwetenschappelijk onderzoek (TNO)
Marcel Leist
Universität Konstanz
Joerg Rahnenfuehrer
Technische Universität Dortmund
Jan G. Hengstler
Leibniz Research Centre for Working Environment and Human Factors at the University of Dortmund
Archives of Toxicology
0340-5761 (ISSN) 1432-0738 (eISSN)
Vol. 88 12 2261-2287Ämneskategorier
Farmakologi och toxikologi
DOI
10.1007/s00204-014-1400-x