NDLI: Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests

Content Provider	Springer Nature Link
Author	Shinde, Vaibhav Hoelting, Lisa Srinivasan, Sureshkumar Perumal Meisig, Johannes Meganathan, Kesavan Jagtap, Smita Grinberg, Marianna Liebing, Julia Bluethgen, Nils Rahnenführer, Jörg Rempel, Eugen Stoeber, Regina Schildknecht, Stefan Förster, Sunniva Godoy, Patricio Thriel, Christoph Gaspar, John Antonydas Hescheler, Jürgen Waldmann, Tanja Hengstler, Jan G. Leist, Marcel Sachinidis, Agapios
Copyright Year	2016
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.
Starting Page	839
Ending Page	864
Page Count	26
File Format	PDF
ISSN	03405761
Journal	Archives of Toxicology
Volume Number	91
Issue Number	2
e-ISSN	14320738
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2016-05-17
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Human stem cells Transcriptome Genomics biomarkers Developmental toxicity In vitro test systems Pharmacology/Toxicology Occupational Medicine/Industrial Medicine Environmental Health Biomedicine
Content Type	Text
Resource Type	Article
Subject	Health, Toxicology and Mutagenesis Medicine Toxicology

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