Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach

Krug, AK; Kolde, R; Gaspar, JA; Rempel, E; Balmer, NV; Meganathan, K; Vojnits, K; Baquié, M; Waldmann, T; Ensenat-Waser, R; Jagtap, S; Evans, RM; Julien, S; Peterson, H; Zagoura, D; Kadereit, S; Gerhard, D; Sotiriadou, I; Heke, M; Natarajan, K ... Sachinidis, A (2013). Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Archives of Toxicology, 87 (1), 123−143.10.1007/s00204-012-0967-3.
ajakirjaartikkel
Krug, AK; Kolde, R; Gaspar, JA; Rempel, E; Balmer, NV; Meganathan, K; Vojnits, K; Baquié, M; Waldmann, T; Ensenat-Waser, R; Jagtap, S; Evans, RM; 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, KH; Hengstler, JG; Rahnenführer, J; Leist, M; Sachinidis, A
  • Inglise
Archives of Toxicology
1432-0738
87
1
2013
123143
Ilmunud
1.1. Teadusartiklid, mis on kajastatud Web of Science andmebaasides Science Citation Index Expanded, Social Sciences Citation Index, Arts & Humanities Citation Index ja/või andmebaasis Scopus (v.a. kogumikud)
WOS

Viited terviktekstile

dx.doi.org/10.1007/s00204-012-0967-3

Lisainfo

Article. M1 - 23179753; L3 - papers://E208B511-C8C3-4CBE-9B00-7574EB76C6DC/Paper/p8201, 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.