Toxicogenomics directory of chemically exposed human hepatocytes
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 map 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 data sets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 148 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics map (http://wiki.toxbank.net/wiki/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The map 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 map 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 were sufficient to induce some stress leading to expression alterations 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 map 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.
The directory informs about the following key features of chemically-influenced genes: (1) Stereotypical stress response. For this purpose the SV value is given for upregulated (SV Up) and downregulated (SV down) genes. The SV value informs how many compounds cause an at least 3-fold up or downregulation of the corresponding gene. (2) Liver disease associated genes. The directory informs, whether the individual genes are upregulated (up), downregulated (down) or unaltered (0) in non-alcoholic steatohepatitis (NASH), liver cirrhosis, or hepatocellular cancer (HCC). Probe sets were listed as up or down when the false discovery rate (FDR) adjusted p-value was smaller than 0.05 and the fold-change was at least 1.3. (3) Unstable baseline genes. The directory informs whether the hepatocyte isolation and cultivation process causes an upregulation (up) or downreglation (down) of the corresponding genes or whether no change was observed (0). 'Up' or 'down' indicates probe sets deregulated in human hepatocytes cultivated in collagen sandwich culture for 1, 2, 3, 5, 7, 10, and 14 days at least a 3-fold at least at one cultivation period. The abbreviated names of the compounds are given, the corresponding full names are given in Table S2. For all 54675 probesets analyzed on the HG-U133 Plus 2-GeneChip the Gene Symbol, Gene Name, Probe set-ID, Entrez-ID, and Ensemble-ID are given. "NA" indicates no annotation.
Data and protocols
The protocols used in the generation and analysis of the data will be available soon at:
The data used in this publication will be available soon at:
Questions, inquiries, comments and feedback regarding the analysis may be directed to the Jan Hengstler at the Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo), 44139 Dortmund, Germany.
The research leading to these results has received funding from Cosmetics Europe and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° .
Copyright / License
All data in this wiki is currently copyrighted by the respective contributors.