Universität zu Köln

Colaianna, Marilena, Ilmjarv, Sten, Peterson, Hedi ORCID: 0000-0001-9951-5116, Kern, Ilse, Julien, Stephanie, Baquie, Mathurin, Pallocca, Giorgia, Bosgra, Sieto, Sachinidis, Agapios, Hengstler, Jan G., Leist, Marcel ORCID: 0000-0002-3778-8693 and Krause, Karl-Heinz ORCID: 0000-0002-9033-6768 (2017). Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay. Arch. Toxicol., 91 (1). S. 365 - 392. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

Full text not available from this repository.

Abstract

Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration-response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration-response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Colaianna, Marilena UNSPECIFIED UNSPECIFIED UNSPECIFIED Ilmjarv, Sten UNSPECIFIED UNSPECIFIED UNSPECIFIED Peterson, Hedi UNSPECIFIED orcid.org/0000-0001-9951-5116 UNSPECIFIED Kern, Ilse UNSPECIFIED UNSPECIFIED UNSPECIFIED Julien, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Baquie, Mathurin UNSPECIFIED UNSPECIFIED UNSPECIFIED Pallocca, Giorgia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bosgra, Sieto UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED Krause, Karl-Heinz UNSPECIFIED orcid.org/0000-0002-9033-6768 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-242974
DOI:	10.1007/s00204-016-1690-2
Journal or Publication Title:	Arch. Toxicol.
Volume:	91
Number:	1
Page Range:	S. 365 - 392
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 HISTONE DEACETYLASE INHIBITOR; COLONY-STIMULATING FACTOR; FETAL VALPROATE SYNDROME; DEVELOPMENTAL NEUROTOXICITY; IN-VITRO; METHYL MERCURY; LUNG-CANCER; PHASE-I; NEURONAL DIFFERENTIATION; MULTIPLE-SCLEROSIS Multiple languages Toxicology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24297