Universität zu Köln

Cherianidou, Anna, Seidel, Florian ORCID: 0000-0002-4466-332X, Kappenberg, Franziska ORCID: 0000-0001-8066-5333, Dreser, Nadine, Blum, Jonathan ORCID: 0000-0002-2058-0511, Waldmann, Tanja ORCID: 0000-0001-9276-1592, Bluethgen, Nils, Meisig, Johannes, Madjar, Katrin ORCID: 0000-0001-6169-8105, Henry, Margit, Rotshteyn, Tamara, Marchan, Rosemarie, Edlund, Karolina, Leist, Marcel ORCID: 0000-0002-3778-8693, Rahnenfuhrer, Joerg, Sachinidis, Agapios and Hengstler, Jan G. (2022). Classification of Developmental Toxicants in a Human iPSC Transcriptomics-Based Test. Chem. Res. Toxicol., 35 (5). S. 760 - 774. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-5010

Full text not available from this repository.

Abstract

Despite the progress made in developmental toxicology, there is a great need for in vitro tests that identify developmental toxicants in relation to human oral doses and blood concentrations. In the present study, we established the hiPSC-based UKK2 in vitro test and analyzed genome-wide expression profiles of 23 known teratogens and 16 non-teratogens. Compounds were analyzed at the maximal plasma concentration (C-max) and at 20-fold C-max for a 24 h incubation period in three independent experiments. Based on the 1000 probe sets with the highest variance and including information on cytotoxicity, penalized logistic regression with leave-one-out cross-validation was used to classify the compounds as test-positive or test-negative, reaching an area under the curve (AUC), accuracy, sensitivity, and specificity of 0.96, 0.92, 0.96, and 0.88, respectively. Omitting the cytotoxicity information reduced the test performance to an AUC of 0.94, an accuracy of 0.79, and a sensitivity of 0.74. A second method, which used the number of significantly deregulated probe sets to classify the compounds, resulted in a specificity of 1; however, the AUC (0.90), accuracy (0.90), and sensitivity (0.83) were inferior compared to those of the logistic regression-based procedure. Finally, no increased performance was achieved when the high test concentrations (20-fold C-max) were used, in comparison to testing within the realistic clinical range (1-fold C-max). In conclusion, although further optimization is required, for example, by including additional readouts and cell systems that model different developmental processes, the UKK2-test in its present form can support the early discovery-phase detection of human developmental toxicants.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Cherianidou, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Seidel, Florian UNSPECIFIED orcid.org/0000-0002-4466-332X UNSPECIFIED Kappenberg, Franziska UNSPECIFIED orcid.org/0000-0001-8066-5333 UNSPECIFIED Dreser, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Blum, Jonathan UNSPECIFIED orcid.org/0000-0002-2058-0511 UNSPECIFIED Waldmann, Tanja UNSPECIFIED orcid.org/0000-0001-9276-1592 UNSPECIFIED Bluethgen, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Meisig, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Madjar, Katrin UNSPECIFIED orcid.org/0000-0001-6169-8105 UNSPECIFIED Henry, Margit UNSPECIFIED UNSPECIFIED UNSPECIFIED Rotshteyn, Tamara UNSPECIFIED UNSPECIFIED UNSPECIFIED Marchan, Rosemarie UNSPECIFIED UNSPECIFIED UNSPECIFIED Edlund, Karolina UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED Rahnenfuhrer, Joerg UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-687181
DOI:	10.1021/acs.chemrestox.1c00392
Journal or Publication Title:	Chem. Res. Toxicol.
Volume:	35
Number:	5
Page Range:	S. 760 - 774
Date:	2022
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1520-5010
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PLURIPOTENT STEM-CELLS; TOXICITY; DIFFERENTIATION; NEUROTOXICITY; EXPRESSION; BIOMARKERS; SIGNATURES; PREGNANCY; DESIGN Multiple languages Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68718