Details
| Original language | English |
|---|---|
| Pages (from-to) | 123-143 |
| Number of pages | 21 |
| Journal | Archives of toxicology |
| Volume | 87 |
| Issue number | 1 |
| Publication status | Published - 21 Nov 2012 |
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.
Keywords
- Alternative testing strategies, Methylmercury, Reproductive toxicity, Transcription factor, Valproic acid
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Toxicology
- Environmental Science(all)
- Health, Toxicology and Mutagenesis
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In: Archives of toxicology, Vol. 87, No. 1, 21.11.2012, p. 123-143.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Human embryonic stem cell-derived test systems for developmental neurotoxicity
T2 - A transcriptomics approach
AU - Krug, Anne K.
AU - Kolde, Raivo
AU - Gaspar, John A.
AU - Rempel, Eugen
AU - Balmer, Nina V.
AU - Meganathan, Kesavan
AU - Vojnits, Kinga
AU - Baquié, Mathurin
AU - Waldmann, Tanja
AU - Ensenat-Waser, Roberto
AU - Jagtap, Smita
AU - Evans, Richard M.
AU - Julien, Stephanie
AU - Peterson, Hedi
AU - Zagoura, Dimitra
AU - Kadereit, Suzanne
AU - Gerhard, Daniel
AU - Sotiriadou, Isaia
AU - Heke, Michael
AU - Natarajan, Karthick
AU - Henry, Margit
AU - Winkler, Johannes
AU - Marchan, Rosemarie
AU - Stoppini, Luc
AU - Bosgra, Sieto
AU - Westerhout, Joost
AU - Verwei, Miriam
AU - Vilo, Jaak
AU - Kortenkamp, Andreas
AU - Hescheler, Jürgen
AU - Hothorn, Ludwig
AU - Bremer, Susanne
AU - Van Thriel, Christoph
AU - Krause, Karl Heinz
AU - Hengstler, Jan G.
AU - Rahnenführer, Jörg
AU - Leist, Marcel
AU - Sachinidis, Agapios
N1 - Funding Information: Acknowledgments This study was funded by the FP7 project ESNATS, the DFG and the Doerenkamp-Zbinden Foundation. We thank Sara Skogsater (ARTTIC) for excellent work in coordinating the ESNATS consortium and for her helpful and professional support of the current study. The great technical assistance of Marion Kapitza is gratefully acknowledged.
PY - 2012/11/21
Y1 - 2012/11/21
N2 - 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.
AB - 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.
KW - Alternative testing strategies
KW - Methylmercury
KW - Reproductive toxicity
KW - Transcription factor
KW - Valproic acid
UR - http://www.scopus.com/inward/record.url?scp=84872346334&partnerID=8YFLogxK
U2 - 10.1007/s00204-012-0967-3
DO - 10.1007/s00204-012-0967-3
M3 - Article
C2 - 23179753
AN - SCOPUS:84872346334
VL - 87
SP - 123
EP - 143
JO - Archives of toxicology
JF - Archives of toxicology
SN - 0340-5761
IS - 1
ER -