Grinberg, Marianna, Stoeber, Regina M., Edlund, Karolina, Rempel, Eugen, Godoy, Patricio, Reif, Raymond, Widera, Agata, Madjar, Katrin ORCID: 0000-0001-6169-8105, Schmidt-Heck, Wolfgang, Marchan, Rosemarie ORCID: 0000-0003-4414-1633, Sachinidis, Agapios, Spitkovsky, Dimitry, Hescheler, Jurgen, Carmo, Helena ORCID: 0000-0002-6650-5285, Arbo, Marcelo D., van de Water, Bob, Wink, Steven, Vinken, Mathieu ORCID: 0000-0001-5115-8893, Rogiers, Vera ORCID: 0000-0003-0635-7740, Escher, Sylvia, Hardy, Barry, Mitic, Dragana, Myatt, Glenn, Waldmann, Tanja, Mardinoglu, Adil, Damm, Georg ORCID: 0000-0002-2104-8076, Seehofer, Daniel, Nuessler, Andreas, Weiss, Thomas S., Oberemm, Axel ORCID: 0000-0002-4355-4404, Lampen, Alfons, Schaap, Mirjam M., Luijten, Mirjam, van Steeg, Harry, Thasler, Wolfgang E., Kleinjans, Jos C. S., Stierum, Rob H., Leist, Marcel ORCID: 0000-0002-3778-8693, Rahnenfuehrer, Joerg and Hengstler, Jan G. (2014). Toxicogenomics directory of chemically exposed human hepatocytes. Arch. Toxicol., 88 (12). S. 2261 - 2288. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Grinberg, MariannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeber, Regina M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Edlund, KarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rempel, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Godoy, PatricioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reif, RaymondUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Widera, AgataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madjar, KatrinUNSPECIFIEDorcid.org/0000-0001-6169-8105UNSPECIFIED
Schmidt-Heck, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marchan, RosemarieUNSPECIFIEDorcid.org/0000-0003-4414-1633UNSPECIFIED
Sachinidis, AgapiosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spitkovsky, DimitryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hescheler, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmo, HelenaUNSPECIFIEDorcid.org/0000-0002-6650-5285UNSPECIFIED
Arbo, Marcelo D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Water, BobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wink, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vinken, MathieuUNSPECIFIEDorcid.org/0000-0001-5115-8893UNSPECIFIED
Rogiers, VeraUNSPECIFIEDorcid.org/0000-0003-0635-7740UNSPECIFIED
Escher, SylviaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardy, BarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mitic, DraganaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myatt, GlennUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waldmann, TanjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mardinoglu, AdilUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damm, GeorgUNSPECIFIEDorcid.org/0000-0002-2104-8076UNSPECIFIED
Seehofer, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuessler, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiss, Thomas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oberemm, AxelUNSPECIFIEDorcid.org/0000-0002-4355-4404UNSPECIFIED
Lampen, AlfonsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaap, Mirjam M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luijten, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Steeg, HarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thasler, Wolfgang E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleinjans, Jos C. S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stierum, Rob H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leist, MarcelUNSPECIFIEDorcid.org/0000-0002-3778-8693UNSPECIFIED
Rahnenfuehrer, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hengstler, Jan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-422361
DOI: 10.1007/s00204-014-1400-x
Journal or Publication Title: Arch. Toxicol.
Volume: 88
Number: 12
Page Range: S. 2261 - 2288
Date: 2014
Publisher: SPRINGER HEIDELBERG
Place of Publication: HEIDELBERG
ISSN: 1432-0738
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE-EXPRESSION ALTERATIONS; IN-VITRO; X-RECEPTOR; RAT-LIVER; PREDICTION; MOUSE; TRANSPORTER; SENSITIVITY; METABOLISM; RESPONSESMultiple languages
ToxicologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/42236

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