Universität zu Köln

Dreser, Nadine ORCID: 0000-0002-7103-0990, Madjar, Katrin ORCID: 0000-0001-6169-8105, Holzer, Anna-Katharina, Kapitza, Marion, Scholz, Christopher, Kranaster, Petra ORCID: 0000-0002-6082-0161, Gutbier, Simon, Klima, Stefanie, Kolb, David, Dietz, Christian, Trefzer, Timo, Meisig, Johannes, van Thriel, Christoph ORCID: 0000-0003-3215-9262, Henry, Margit, Berthold, Michael R., Bluethgen, Nils, Sachinidis, Agapios, Rahnenfuehrer, Joerg, Hengstler, Jan G., Waldmann, Tanja and Leist, Marcel ORCID: 0000-0002-3778-8693 (2020). Development of a neural rosette formation assay (RoFA) to identify neurodevelopmental toxicants and to characterize their transcriptome disturbances. Arch. Toxicol., 94 (1). S. 151 - 172. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpoints. To address this issue, we developed a new version of the human stem cell-based test STOP-tox((UKN)). For this purpose, the capacity of the cells to self-organize to neural rosettes was assessed as functional endpoint: pluripotent stem cells were allowed to differentiate into neuroepithelial cells for 6 days in the presence or absence of toxicants. Then, both transcriptome changes were measured (standard STOP-tox((UKN))) and cells were allowed to form rosettes. After optimization of staining methods, an imaging algorithm for rosette quantification was implemented and used for an automated rosette formation assay (RoFA). Neural tube toxicants (like valproic acid), which are known to disturb human development at stages when rosette-forming cells are present, were used as positive controls. Established toxicants led to distinctly different tissue organization and differentiation stages. RoFA outcome and transcript changes largely correlated concerning (1) the concentration-dependence, (2) the time dependence, and (3) the set of positive hits identified amongst 24 potential toxicants. Using such comparative data, a prediction model for the RoFA was developed. The comparative analysis was also used to identify gene dysregulations that are particularly predictive for disturbed rosette formation. This 'RoFA predictor gene set' may be used for a simplified and less costly setup of the STOP-tox((UKN)) assay.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dreser, Nadine UNSPECIFIED orcid.org/0000-0002-7103-0990 UNSPECIFIED Madjar, Katrin UNSPECIFIED orcid.org/0000-0001-6169-8105 UNSPECIFIED Holzer, Anna-Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Kapitza, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Scholz, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED Kranaster, Petra UNSPECIFIED orcid.org/0000-0002-6082-0161 UNSPECIFIED Gutbier, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Klima, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolb, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietz, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Trefzer, Timo UNSPECIFIED UNSPECIFIED UNSPECIFIED Meisig, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED van Thriel, Christoph UNSPECIFIED orcid.org/0000-0003-3215-9262 UNSPECIFIED Henry, Margit UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Michael R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bluethgen, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuehrer, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-127844
DOI:	10.1007/s00204-019-02612-5
Journal or Publication Title:	Arch. Toxicol.
Volume:	94
Number:	1
Page Range:	S. 151 - 172
Date:	2020
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EMBRYONIC STEM-CELLS; NEUROTOXICITY DNT; GENE-EXPRESSION; TERATOGENICITY TEST; NEURITE OUTGROWTH; ZEBRAFISH EMBRYO; CREST MIGRATION; HUMAN ES; VALIDATION; MODEL Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12784