Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach.
Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach.
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DOI：
10.1007/s00204-012-0967-3
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发表时间：
2013-01
影响因子：
6.1
通讯作者：
Sachinidis, Agapios
中科院分区：
文献类型：
--
作者：
Krug, Anne K.;Kolde, Raivo;Gaspar, John A.;Rempel, Eugen;Balmer, Nina V.;Meganathan, Kesavan;Vojnits, Kinga;Baquie, Mathurin;Waldmann, Tanja;Ensenat-Waser, Roberto;Jagtap, Smita;Evans, Richard M.;Julien, Stephanie;Peterson, Hedi;Zagoura, Dimitra;Kadereit, Suzanne;Gerhard, Daniel;Sotiriadou, Isaia;Heke, Michael;Natarajan, Karthick;Henry, Margit;Winkler, Johannes;Marchan, Rosemarie;Stoppini, Luc;Bosgra, Sieto;Westerhout, Joost;Verwei, Miriam;Vilo, Jaak;Kortenkamp, Andreas;Hescheler, Jurgen;Hothorn, Ludwig;Bremer, Susanne;van Thriel, Christoph;Krause, Karl-Heinz;Hengstler, Jan G.;Rahnenfuehrer, Jorg;Leist, Marcel;Sachinidis, Agapios
关键词：
发育神经毒性（DNT）和许多形式的生殖毒性（RT）通常表现为功能缺陷，这些功能缺陷不一定是基于细胞死亡，而是与细胞分化或通讯相关的微小变化。 DNT/RT 领域将极大地受益于体外测试，这些测试可以识别毒物诱导的细胞蛋白质稳态或其潜在转录组网络的变化。因此，“人类胚胎干细胞（hESC）衍生的新型替代测试系统（ESNATS）”欧盟委员会研究项目根据hESC及其后代的明确分化方案建立了RT测试。使用丙戊酸（VPA）和甲基汞（MeHg）作为阳性对照化合物来解决以下基本问题：（1）转录组分析是否可以区分这两种化合物？ (2) 富集转录因子结合位点 (TFBS) 和单个探针组 (PS) 的分析如何区分测试系统？ （3）批次效应能否控制？ (4) 需要多少个DNA微阵列？ (5) 最高的非细胞毒性浓度对于转录组变化的研究是否最佳且相关？ VPA 引发巨大的转录变化，而 MeHg 改变的转录物较少。为了减弱批次效应，分析重点关注变异性最高的 500 PS。测试系统的响应存在显着差异（<20% 重叠）。此外，在一个测试系统中，观察到两种化合物改变的 PS 之间几乎没有重叠。然而，使用 TFBS 富集，可以将 VPA 和 MeHg 的相对较大的“共同反应”与“化合物特异性”反应区分开来。总之，ESNATS 检测组合允许根据转录组图谱对人类 DNT/RT 毒物进行分类。本文的在线版本 (doi:10.1007/s00204-012-0967-3) 包含补充材料，可供授权用户使用。
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 online version of this article (doi:10.1007/s00204-012-0967-3) contains supplementary material, which is available to authorized users.
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影响因子：
3.5
作者：
Balmer, Nina V.;Weng, Matthias K.;Leist, Marcel
通讯作者：
Leist, Marcel
影响因子：
2.8
作者：
Forsby, Anna;Blaauboer, Bas
通讯作者：
Blaauboer, Bas
影响因子：
46.9
作者：
Chambers, Stuart M.;Fasano, Christopher A.;Papapetrou, Eirini P.;Tomishima, Mark;Sadelain, Michel;Studer, Lorenz
通讯作者：
Studer, Lorenz
DOI：
10.1016/0272-0590(88)90112-1
发表时间：
1988-10-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
BINKERD, PE;ROWLAND, JM;HENDRICKX, AG
通讯作者：
HENDRICKX, AG
影响因子：
7.3
作者：
Jagtap, S.;Meganathan, K.;Sachinidis, A.
通讯作者：
Sachinidis, A.