Human embryonic stem cell-derived test systems for developmental neurotoxicity: A transcriptomics approach
Creators: name: Krug, Anne K.
name: Kolde, Raivo
name: Gaspar, John A.
name: Rempel, Eugen
name: Balmer, Nina V.
name: Meganathan, Kesavan
name: Vojnits, Kinga
name: Baquié, Mathurin
name: Waldmann, Tanja
name: Ensenat-Waser, Roberto
name: Jagtap, Smita
name: Evans, Richard M.
name: Julien, Stephanie
name: Peterson, Hedi
name: Zagoura, Dimitra
name: Kadereit, Suzanne
name: Gerhard, Daniel
name: Sotiriadou, Isaia
name: Heke, Michael
name: Natarajan, Karthick
name: Henry, Margit
name: Winkler, Johannes
name: Marchan, Rosemarie
name: Stoppini, Luc
name: Bosgra, Sieto
name: Westerhout, Joost
name: Verwei, Miriam
name: Vilo, Jaak
name: Kortenkamp, Andreas
name: Hescheler, Jürgen
name: Hothorn, Ludwig A.
name: Bremer, Susanne
name: Van Thriel, Christoph
name: Krause, Karl-Heinz
name: Hengstler, Jan G.
name: Rahnenführer, Jörg
name: Leist, Marcel
name: Sachinidis, Agapios
Publisher: name: Heidelberg : Springer Verlag
Year: 2013
Subjects: subject: Alternative testing strategies
subject: Methylmercury
subject: Reproductive toxicity
subject: Transcription factor
subject: Valproic acid
subject: methylmercury
subject: transcription factor
subject: valproic acid
subject: article
subject: binding site
subject: classification algorithm
subject: controlled study
subject: developmental toxicity
subject: DNA microarray
subject: embryonic stem cell
subject: human
subject: human cell
subject: neurotoxicity
subject: priority journal
subject: toxicity testing
subject: transcription factor binding site
subject: transcriptomics
subject: Binding Sites
subject: Cells, Cultured
subject: Embryonic Stem Cells
subject: Gene Expression Profiling
subject: Gene Expression Regulation
subject: Humans
subject: Methylmercury Compounds
subject: Mutagenicity Tests
subject: Neurotoxicity Syndromes
subject: Oligonucleotide Array Sequence Analysis
subject: Valproic Acid
subject: Dewey Decimal Classification::500 | Naturwissenschaften::570 | Biowissenschaften, Biologie
subject: Dewey Decimal Classification::600 | Technik::610 | Medizin, Gesundheit

description: Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification of toxicant-induced changes of the cellular proteostasis, or of its underlying transcriptome network. Therefore, the 'human embryonic stem cell (hESC)- derived novel alternative test systems (ESNATS)' European commission research project established RT tests based on defined differentiation protocols of hESC and their progeny. Valproic acid (VPA) and methylmercury (MeHg) were used as positive control compounds to address the following fundamental questions: (1) Does transcriptome analysis allow discrimination of the two compounds? (2) How does analysis of enriched transcription factor binding sites (TFBS) and of individual probe sets (PS) distinguish between test systems? (3) Can batch effects be controlled? (4) How many DNA microarrays are needed? (5) Is the highest non-cytotoxic concentration optimal and relevant for the study of transcriptome changes? VPA triggered vast transcriptional changes, whereas MeHg altered fewer transcripts. To attenuate batch effects, analysis has been focused on the 500 PS with highest variability. The test systems differed significantly in their responses (\20 % overlap). Moreover, within one test system, little overlap between the PS changed by the two compounds has been observed. However, using TFBS enrichment, a relatively large 'common response' to VPA and MeHg could be distinguished from 'compound-specific' responses. In conclusion, the ESNATS assay battery allows classification of human DNT/RT toxicants on the basis of their transcriptome profiles.