Title
Human embryonic stem cell-derived test systems for developmental neurotoxicity: A transcriptomics approach
Author
Krug, A.K.
Kolde, R.
Gaspar, J.A.
Rempel, E.
Balmer, N.V.
Meganathan, K.
Vojnits, K.
Baquié, M.
Waldmann, T.
Ensenat-Waser, R.
Jagtap, S.
Evans, R.M.
Julien, S.
Peterson, H.
Zagoura, D.
Kadereit, S.
Gerhard, D.
Sotiriadou, I.
Heke, M.
Natarajan, K.
Henry, M.
Winkler, J.
Marchan, R.
Stoppini, L.
Bosgra, S.
Westerhout, J.
Verwei, M.
Vilo, J.
Kortenkamp, A.
Hescheler, J.
Hothorn, L.
Bremer, S.
van Thriel, C.
Krause, K.-H.
Hengstler, J.G.
Rahnenführer, J.
Leist, M.
Sachinidis, A.
Publication year
2013
Abstract
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. © The Author(s) 2012.
Subject
Life
PHS - Pharmacokinetics & Human Studies
EELS - Earth, Environmental and Life Sciences
Biology
Healthy Living
Alternative testing strategies
Methylmercury
Reproductive toxicity
Transcription factor
Valproic acid
To reference this document use:
http://resolver.tudelft.nl/uuid:15a16318-d5cf-4e01-9823-7e078294d390
DOI
https://doi.org/10.1007/s00204-012-0967-3
TNO identifier
469526
ISSN
0340-5761
Source
Archives of Toxicology, 87 (1), 123-143
Document type
article