A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors

  1. Rempel, Eugen
  2. Hoelting, Lisa
  3. Waldmann, Tanja
  4. Balmer, Nina V.
  5. Schildknecht, Stefan
  6. Grinberg, Marianna
  7. Gaspar, John Antony Das
  8. Shinde, Vaibhav
  9. Stöber, Regina
  10. Meisig, Johannes
  11. Blüthgen, Nils
  12. Sachinidis, Agapios
  13. Rahnenführer, Jörg
  14. Leist, Marcel
  15. Marchan, Rosemarie ORCID logo
  16. van Thriel, Christoph ORCID logo
  17. http://d-nb.info/gnd/111570012X
  18. Hengstler, Jan G.

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WeightNameValue
1000 Titel
  • A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors
1000 Autor/in
  1. Rempel, Eugen |
  2. Hoelting, Lisa |
  3. Waldmann, Tanja |
  4. Balmer, Nina V. |
  5. Schildknecht, Stefan |
  6. Grinberg, Marianna |
  7. Gaspar, John Antony Das |
  8. Shinde, Vaibhav |
  9. Stöber, Regina |
  10. Meisig, Johannes |
  11. Blüthgen, Nils |
  12. Sachinidis, Agapios |
  13. Rahnenführer, Jörg |
  14. Leist, Marcel |
  15. Marchan, Rosemarie |
  16. van Thriel, Christoph |
  17. http://d-nb.info/gnd/111570012X |
  18. Hengstler, Jan G. |
1000 Erscheinungsjahr 2015
1000 LeibnizOpen
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2015-08-14
1000 Erschienen in
1000 Quellenangabe
  • 89(9): 1599–1618
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2015
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s00204-015-1573-y |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551554/ |
1000 Ergänzendes Material
  • https://link.springer.com/article/10.1007%2Fs00204-015-1573-y#SupplementaryMaterial |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Test systems to identify developmental toxicants are urgently needed. A combination of human stem cell technology and transcriptome analysis was to provide a proof of concept that toxicants with a related mode of action can be identified and grouped for read-across. We chose a test system of developmental toxicity, related to the generation of neuroectoderm from pluripotent stem cells (UKN1), and exposed cells for 6 days to the histone deacetylase inhibitors (HDACi) valproic acid, trichostatin A, vorinostat, belinostat, panobinostat and entinostat. To provide insight into their toxic action, we identified HDACi consensus genes, assigned them to superordinate biological processes and mapped them to a human transcription factor network constructed from hundreds of transcriptome data sets. We also tested a heterogeneous group of ‘mercurials’ (methylmercury, thimerosal, mercury(II)chloride, mercury(II)bromide, 4-chloromercuribenzoic acid, phenylmercuric acid). Microarray data were compared at the highest non-cytotoxic concentration for all 12 toxicants. A support vector machine (SVM)-based classifier predicted all HDACi correctly. For validation, the classifier was applied to legacy data sets of HDACi, and for each exposure situation, the SVM predictions correlated with the developmental toxicity. Finally, optimization of the classifier based on 100 probe sets showed that eight genes (F2RL2, TFAP2B, EDNRA, FOXD3, SIX3, MT1E, ETS1 and LHX2) are sufficient to separate HDACi from mercurials. Our data demonstrate how human stem cells and transcriptome analysis can be combined for mechanistic grouping and prediction of toxicants. Extension of this concept to mechanisms beyond HDACi would allow prediction of human developmental toxicity hazard of unknown compounds with the UKN1 test system.
1000 Sacherschließung
lokal Alternative testing
lokal Hazard assessment
lokal Cytotoxicity
lokal Neuronal development
lokal Transcriptomics
lokal Developing central nervous system
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/UmVtcGVsLCBFdWdlbg==|https://frl.publisso.de/adhoc/creator/SG9lbHRpbmcsIExpc2E=|https://frl.publisso.de/adhoc/creator/V2FsZG1hbm4sIFRhbmph|https://frl.publisso.de/adhoc/creator/QmFsbWVyLCBOaW5hwqBWLg==|https://frl.publisso.de/adhoc/creator/U2NoaWxka25lY2h0LCBTdGVmYW4=|https://frl.publisso.de/adhoc/creator/R3JpbmJlcmcsIE1hcmlhbm5h|https://frl.publisso.de/adhoc/creator/R2FzcGFyLCBKb2huwqBBbnRvbnnCoERhcw==|https://frl.publisso.de/adhoc/creator/U2hpbmRlLCBWYWliaGF2|https://frl.publisso.de/adhoc/creator/U3TDtmJlciwgUmVnaW5h|https://frl.publisso.de/adhoc/creator/TWVpc2lnLCBKb2hhbm5lcw==|https://frl.publisso.de/adhoc/creator/QmzDvHRoZ2VuLCBOaWxz|https://frl.publisso.de/adhoc/creator/U2FjaGluaWRpcywgQWdhcGlvcw==|https://frl.publisso.de/adhoc/creator/UmFobmVuZsO8aHJlciwgSsO2cmc=|https://frl.publisso.de/adhoc/creator/TGVpc3QsIE1hcmNlbA==|http://orcid.org/0000-0003-4414-1633|http://orcid.org/0000-0003-3215-9262|http://d-nb.info/gnd/111570012X|http://d-nb.info/gnd/175862257
1000 Label
1000 Förderer
  1. German Federal Ministry of Education and Research (BMBF) |
  2. European Union |
  3. graduate schools |
1000 Fördernummer
  1. -
  2. -
  3. RTG1331; KoRS-CB
1000 Förderprogramm
  1. project SysDT
  2. project ESNATS
  3. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer German Federal Ministry of Education and Research (BMBF) |
    1000 Förderprogramm project SysDT
    1000 Fördernummer -
  2. 1000 joinedFunding-child
    1000 Förderer European Union |
    1000 Förderprogramm project ESNATS
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer graduate schools |
    1000 Förderprogramm -
    1000 Fördernummer RTG1331; KoRS-CB
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6404979.rdf
1000 Erstellt am 2017-10-12T17:56:47.210+0200
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1000 Zuletzt bearbeitet Fri Dec 04 12:12:39 CET 2020
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