Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach
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- 作者：Anne K. Krug (1)
Raivo Kolde (2) (3)
John A. Gaspar (4)
Eugen Rempel (11)
Nina V. Balmer (1)
Kesavan Meganathan (4)
Kinga Vojnits (6)
Mathurin Baquié (7)
Tanja Waldmann (1)
Roberto Ensenat-Waser (6)
Smita Jagtap (4)
Richard M. Evans (8)
Stephanie Julien (7)
Hedi Peterson (7)
Dimitra Zagoura (6)
Suzanne Kadereit (1)
Daniel Gerhard (10)
Isaia Sotiriadou (4)
Michael Heke (4)
Karthick Natarajan (4)
Margit Henry (4)
Johannes Winkler (4)
Rosemarie Marchan (5)
Luc Stoppini (7)
Sieto Bosgra (9)
Joost Westerhout (9)
Miriam Verwei (9)
Jaak Vilo (2) (3)
Andreas Kortenkamp (8)
Jürgen Hescheler (4)
Ludwig Hothorn (10)
Susanne Bremer (6)
Christoph van Thriel (5)
Karl-Heinz Krause (7)
Jan G. Hengstler (5)
J?rg Rahnenführer (11)
Marcel Leist (1)
Agapios Sachinidis (4) - 关键词：Methylmercury ; Valproic acid ; Transcription factor ; Reproductive toxicity ; Alternative testing strategies
- 刊名：Archives of Toxicology
- 出版年：2013
- 出版时间：January 2013
- 年：2013
- 卷：87
- 期：1
- 页码：123-143
- 全文大小：1270KB
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Raivo Kolde (2) (3)
John A. Gaspar (4)
Eugen Rempel (11)
Nina V. Balmer (1)
Kesavan Meganathan (4)
Kinga Vojnits (6)
Mathurin Baquié (7)
Tanja Waldmann (1)
Roberto Ensenat-Waser (6)
Smita Jagtap (4)
Richard M. Evans (8)
Stephanie Julien (7)
Hedi Peterson (7)
Dimitra Zagoura (6)
Suzanne Kadereit (1)
Daniel Gerhard (10)
Isaia Sotiriadou (4)
Michael Heke (4)
Karthick Natarajan (4)
Margit Henry (4)
Johannes Winkler (4)
Rosemarie Marchan (5)
Luc Stoppini (7)
Sieto Bosgra (9)
Joost Westerhout (9)
Miriam Verwei (9)
Jaak Vilo (2) (3)
Andreas Kortenkamp (8)
Jürgen Hescheler (4)
Ludwig Hothorn (10)
Susanne Bremer (6)
Christoph van Thriel (5)
Karl-Heinz Krause (7)
Jan G. Hengstler (5)
J?rg Rahnenführer (11)
Marcel Leist (1)
Agapios Sachinidis (4)
1. Department of Biology, University of Konstanz (UKN), 78457, Constance, Germany
2. Oü Quretec (Qure), Limited Liability Company, 51003, Tartu, Estonia
3. Institute of Computer Science, University of Tartu, 50409, Tartu, Estonia
4. Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne (UKK), Robert-Koch-Str. 39, 50931, Cologne, Germany
11. Department of Statistics, TU Dortmund University, 44221, Dortmund, Germany
6. Commission of the European Communities (JRC) Joint Research Centre, 1049, Brussels, Belgium
7. Department of Pathology and Immunology, Geneva Medical Faculty, University of Geneva (UNIGE), 1211, Geneva 4, Switzerland
8. Brunel University (Brunel), Uxbridge, UB8 3PH, UK
10. Gottfried Wilhelm Leibniz University (LUH), Institute for Biostatistics, 30167, Hannover, Germany
5. Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, 44139, Dortmund, Germany
9. Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek (TNO), 2628 VK, Delft, The Netherlands - ISSN：1432-0738
文摘
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.