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.

Hepatotoxicity

Toxicotranscriptomics

In vivo validation

SEURAT-1

Hepatocellular cancer

Steatosis

Unsupervised clustering

Bioinformatics

Biomarker identification

Cirrhosis

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, Systembiologi

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

National Institute of Public Health and the Environment

Mirjam Luijten

National Institute of Public Health and the Environment

Harry van Steeg

National Institute of 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 2261-2287

Ämneskategorier

Farmakologi och toxikologi

DOI

10.1007/s00204-014-1400-x