Universität zu Köln

Waldmann, Tanja ORCID: 0000-0001-9276-1592, Grinberg, Marianna, Konig, Andre, Rempel, Eugen, Schildknecht, Stefan, Henry, Margit, Holzer, Anna-Katharina, Dreser, Nadine, Shinde, Vaibhav, Sachinidis, Agapios, Rahnenfuhrer, Jorg ORCID: 0000-0002-8947-440X, Hengstler, Jan G. and Leist, Marcel ORCID: 0000-0002-3778-8693 (2017). Stem Cell Transcriptome Responses and Corresponding Biomarkers That Indicate the Transition from Adaptive Responses to Cytotoxicity. Chem. Res. Toxicol., 30 (4). S. 905 - 923. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-5010

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Abstract

Analysis of transcriptome changes has become an established method to characterize the reaction of cells to toxicants. Such experiments are mostly performed at compound concentrations close to the cytotoxicity threshold. At present, little information is available on concentration-dependent features of transcriptome changes, in particular, at the transition from noncytotoxic concentrations to conditions that are associated with cell death. Thus, it is unclear in how far cell death confounds the results of transcriptome studies. To explore this gap of knowledge, we treated pluripotent stem cells differentiating to human neuroepithelial cells (UKN1 assay) for short periods (48 h) with increasing concentrations of valproic acid (VPA) and methyl mercury (MeHg), two compounds with vastly different modes of action. We developed various visualization tools to describe cellular responses, and the overall response was classified as tolerance (minor transcriptome changes), functional adaptation (moderate/strong transcriptome responses, but no cytotoxicity), and degeneration. The latter two conditions were compared, using various statistical approaches. We identified (i) genes regulated at cytotoxic, but not at noncytotoxic, concentrations and (ii) KEGG pathways, gene ontology term groups, and superordinate biological processes that were only regulated at cytotoxic concentrations. The consensus markers and processes found after 48 h treatment were then overlaid with those found after prolonged (6 days) treatment. The study highlights the importance of careful concentration selection and of controlling viability for transcriptome studies. Moreover, it allowed identification of 39 candidate biomarkers of cytotoxicity. These could serve to provide alerts that data sets of interest may have been affected by cell death in the model system studied.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Waldmann, Tanja UNSPECIFIED orcid.org/0000-0001-9276-1592 UNSPECIFIED Grinberg, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Konig, Andre UNSPECIFIED UNSPECIFIED UNSPECIFIED Rempel, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildknecht, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Henry, Margit UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzer, Anna-Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dreser, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Shinde, Vaibhav UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuhrer, Jorg UNSPECIFIED orcid.org/0000-0002-8947-440X UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-235869
DOI:	10.1021/acs.chemrestox.6b00259
Journal or Publication Title:	Chem. Res. Toxicol.
Volume:	30
Number:	4
Page Range:	S. 905 - 923
Date:	2017
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-5010
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-EXPRESSION; IN-VITRO; DEVELOPMENTAL NEUROTOXICITY; SYSTEMS TOXICOLOGY; KYOTO ENCYCLOPEDIA; DOSE-RESPONSE; VALPROIC ACID; TOXICOGENOMICS; TOXICITY; DIFFERENTIATION Multiple languages Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/23586