Toxicogenomics directory of chemically exposed human hepatocytes
Journal article, 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.
Bioinformatics
Biomarker identification
Unsupervised clustering
In vivo validation
Toxicotranscriptomics
Steatosis
Cirrhosis
SEURAT-1
Hepatocellular cancer
Hepatotoxicity
Author
Marianna Grinberg
Technische Universität Dortmund
Regina M. Stoeber
Leibniz Association
K. Edlund
Leibniz Association
Eugen Rempel
Technische Universität Dortmund
Patricio Godoy
Leibniz Association
Raymond Reif
Leibniz Association
Agata Widera
Leibniz Association
Katrin Madjar
Technische Universität Dortmund
Wolfgang Schmidt-Heck
Hans-Knoll-Institute (HKI)
Rosemarie Marchan
Leibniz Association
Agapios Sachinidis
University of Cologne
Dimitry Spitkovsky
University of Cologne
Jurgen Hescheler
University of Cologne
Helena Carmo
University of Porto
Marcelo D. Arbo
University of Porto
Bob van de Water
Leiden University
Steven Wink
Leiden University
Mathieu Vinken
Vrije Universiteit Brussel (VUB)
Vera Rogiers
Vrije Universiteit Brussel (VUB)
Sylvia Escher
Fraunhofer Society
Barry Hardy
Dragana Mitic
Cambridge Cell Networks Ltd
Glenn Myatt
Leadscope
Tanja Waldmann
University of Konstanz
Adil Mardinoglu
Chalmers, Chemical and Biological Engineering, Life Sciences
Georg Damm
Charité University Medicine Berlin
Daniel Seehofer
Charité University Medicine Berlin
Andreas Nuessler
University of Tübingen
Thomas S. Weiss
University of Regensburg
Axel Oberemm
Bundesinstitut Fuer Risikobewertung
Alfons Lampen
Bundesinstitut Fuer Risikobewertung
Mirjam M. Schaap
Netherlands National Institute for Public Health and the Environment
Mirjam Luijten
Netherlands National Institute for Public Health and the Environment
Harry van Steeg
Netherlands National Institute for Public Health and the Environment
Wolfgang E. Thasler
Klinikum der Universitat Munchen
Jos C. S. Kleinjans
Maastricht University
Rob H. Stierum
Netherlands Organisation for Applied Scientific Research (TNO)
Marcel Leist
University of Konstanz
Joerg Rahnenfuehrer
Technische Universität Dortmund
Jan G. Hengstler
Leibniz Association
Archives of Toxicology
0340-5761 (ISSN) 1432-0738 (eISSN)
Vol. 88 12 2261-2287Subject Categories (SSIF 2011)
Pharmacology and Toxicology
DOI
10.1007/s00204-014-1400-x