Universität zu Köln

Shinde, Vaibhav, Hoelting, Lisa, Srinivasan, Sureshkumar Perumal, Meisig, Johannes, Meganathan, Kesavan, Jagtap, Smita, Grinberg, Marianna, Liebing, Julia, Bluethgen, Nils, Rahnenfuehrer, Joerg, Rempel, Eugen, Stoeber, Regina, Schildknecht, Stefan, Foerster, Sunniva, Godoy, Patricio, van Thriel, Christoph ORCID: 0000-0003-3215-9262, Gaspar, John Antonydas, Hescheler, Juergen, Waldmann, Tanja, Hengstler, Jan G., Leist, Marcel ORCID: 0000-0002-3778-8693 and Sachinidis, Agapios (2017). Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Tox(ukn) and STOP-Tox(ukk) tests. Arch. Toxicol., 91 (2). S. 839 - 865. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

Stem cell-based in vitro test systems can recapitulate specific phases of human development. In the UKK test system, human pluripotent stem cells (hPSCs) randomly differentiate into cells of the three germ layers and their derivatives. In the UKN1 test system, hPSCs differentiate into early neural precursor cells. During the normal differentiation period (14 days) of the UKK system, 570 genes [849 probe sets (PSs)] were regulated > fivefold; in the UKN1 system (6 days), 879 genes (1238 PSs) were regulated. We refer to these genes as 'developmental genes'. In the present study, we used genome-wide expression data of 12 test substances in the UKK and UKN1 test systems to understand the basic principles of how chemicals interfere with the spontaneous transcriptional development in both test systems. The set of test compounds included six histone deacetylase inhibitors (HDACis), six mercury-containing compounds ('mercurials') and thalidomide. All compounds were tested at the maximum non-cytotoxic concentration, while valproic acid and thalidomide were additionally tested over a wide range of concentrations. In total, 242 genes (252 PSs) in the UKK test system and 793 genes (1092 PSs) in the UKN1 test system were deregulated by the 12 test compounds. We identified sets of 'diagnostic genes' appropriate for the identification of the influence of HDACis or mercurials. Test compounds that interfered with the expression of developmental genes usually antagonized their spontaneous development, meaning that up-regulated developmental genes were suppressed and developmental genes whose expression normally decreases were induced. The fraction of compromised developmental genes varied widely between the test compounds, and it reached up to 60 %. To quantitatively describe disturbed development on a genome-wide basis, we recommend a concept of two indices, 'developmental potency' (D (p)) and 'developmental index' (D (i)), whereby D (p) is the fraction of all developmental genes that are up- or down-regulated by a test compound, and D (i) is the ratio of overrepresentation of developmental genes among all genes deregulated by a test compound. The use of D (i) makes hazard identification more sensitive because some compounds compromise the expression of only a relatively small number of genes but have a high propensity to deregulate developmental genes specifically, resulting in a low D (p) but a high D (i). In conclusion, the concept based on the indices D (p) and D (i) offers the possibility to quantitatively express the propensity of test compounds to interfere with normal development.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Shinde, Vaibhav UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoelting, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Srinivasan, Sureshkumar Perumal UNSPECIFIED UNSPECIFIED UNSPECIFIED Meisig, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Meganathan, Kesavan UNSPECIFIED UNSPECIFIED UNSPECIFIED Jagtap, Smita UNSPECIFIED UNSPECIFIED UNSPECIFIED Grinberg, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebing, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bluethgen, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuehrer, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Rempel, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Stoeber, Regina UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildknecht, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Foerster, Sunniva UNSPECIFIED UNSPECIFIED UNSPECIFIED Godoy, Patricio UNSPECIFIED UNSPECIFIED UNSPECIFIED van Thriel, Christoph UNSPECIFIED orcid.org/0000-0003-3215-9262 UNSPECIFIED Gaspar, John Antonydas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hescheler, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-241527
DOI:	10.1007/s00204-016-1741-8
Journal or Publication Title:	Arch. Toxicol.
Volume:	91
Number:	2
Page Range:	S. 839 - 865
Date:	2017
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language TEST SYSTEMS; SELENOPROTEIN-W; NONCODING RNA; GBE1 MUTATION; GENE; DISEASE; EXPRESSION; METHYLMERCURY; NEUROTOXICITY; DIFFERENTIATION Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24152