Universität zu Köln

Rempel, Eugen, Hoelting, Lisa, Waldmann, Tanja, Balmer, Nina V., Schildknecht, Stefan, Grinberg, Marianna, Das Gaspar, John Antony, Shinde, Vaibhav, Stoeber, Regina, Marchan, Rosemarie ORCID: 0000-0003-4414-1633, van Thriel, Christoph ORCID: 0000-0003-3215-9262, Liebing, Julia ORCID: 0000-0002-3469-4616, Meisig, Johannes, Bluethgen, Nils, Sachinidis, Agapios, Rahnenfuehrer, Jorg, Hengstler, Jan G. and Leist, Marcel ORCID: 0000-0002-3778-8693 (2015). A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch. Toxicol., 89 (9). S. 1599 - 1619. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

Test systems to identify developmental toxicants are urgently needed. A combination of human stem cell technology and transcriptome analysis was to provide a proof of concept that toxicants with a related mode of action can be identified and grouped for read-across. We chose a test system of developmental toxicity, related to the generation of neuroectoderm from pluripotent stem cells (UKN1), and exposed cells for 6 days to the histone deacetylase inhibitors (HDACi) valproic acid, trichostatin A, vorinostat, belinostat, panobinostat and entinostat. To provide insight into their toxic action, we identified HDACi consensus genes, assigned them to superordinate biological processes and mapped them to a human transcription factor network constructed from hundreds of transcriptome data sets. We also tested a heterogeneous group of 'mercurials' (methylmercury, thimerosal, mercury(II)chloride, mercury(II)bromide, 4-chloromercuribenzoic acid, phenylmercuric acid). Microarray data were compared at the highest non-cytotoxic concentration for all 12 toxicants. A support vector machine (SVM)-based classifier predicted all HDACi correctly. For validation, the classifier was applied to legacy data sets of HDACi, and for each exposure situation, the SVM predictions correlated with the developmental toxicity. Finally, optimization of the classifier based on 100 probe sets showed that eight genes (F2RL2, TFAP2B, EDNRA, FOXD3, SIX3, MT1E, ETS1 and LHX2) are sufficient to separate HDACi from mercurials. Our data demonstrate how human stem cells and transcriptome analysis can be combined for mechanistic grouping and prediction of toxicants. Extension of this concept to mechanisms beyond HDACi would allow prediction of human developmental toxicity hazard of unknown compounds with the UKN1 test system.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rempel, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelting, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Balmer, Nina V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildknecht, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Grinberg, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Das Gaspar, John Antony UNSPECIFIED UNSPECIFIED UNSPECIFIED Shinde, Vaibhav UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoeber, Regina UNSPECIFIED UNSPECIFIED UNSPECIFIED Marchan, Rosemarie UNSPECIFIED orcid.org/0000-0003-4414-1633 UNSPECIFIED van Thriel, Christoph UNSPECIFIED orcid.org/0000-0003-3215-9262 UNSPECIFIED Liebing, Julia UNSPECIFIED orcid.org/0000-0002-3469-4616 UNSPECIFIED Meisig, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Bluethgen, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuehrer, Jorg UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-395225
DOI:	10.1007/s00204-015-1573-y
Journal or Publication Title:	Arch. Toxicol.
Volume:	89
Number:	9
Page Range:	S. 1599 - 1619
Date:	2015
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEURAL-TUBE CLOSURE; IN-VITRO; VALPROIC ACID; MINAMATA DISEASE; MOUSE MUTANTS; TEST SYSTEMS; NEUROTOXICITY; EXPRESSION; METHYLMERCURY; DEFECTS Multiple languages Toxicology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39522