title: Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.
abstract: The in vitro test battery of the European research consortium ESNATS ('novel stem cell-based test systems') has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow-up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.
authors.affiliation: Department of In Vitro Toxicology and Biomedicine, University of Konstanz, Box 657, 78457, Constance, Germany. giorgia.pallocca@uni-konstanz.de.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pallocca
authors.affiliation: Department of Statistics, TU Dortmund University, 44139, Dortmund, Germany.
authors.forename: Marianna
authors.initials: M
authors.lastname: Grinberg
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, 50931, Cologne, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Henry
authors.affiliation: Department of Bioinformatics, University of Konstanz, 78457, Constance, Germany.
authors.forename: Tancred
authors.initials: T
authors.lastname: Frickey
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund, 44139, Dortmund, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Department of In Vitro Toxicology and Biomedicine, University of Konstanz, Box 657, 78457, Constance, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Waldmann
authors.affiliation: Department of Bioinformatics, University of Konstanz, 78457, Constance, Germany.
authors.forename: Agapios
authors.initials: A
authors.lastname: Sachinidis
authors.affiliation: Department of Statistics, TU Dortmund University, 44139, Dortmund, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.affiliation: Department of In Vitro Toxicology and Biomedicine, University of Konstanz, Box 657, 78457, Constance, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
mesh_terms: D000826:Animal Testing Alternatives; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D019295:Computational Biology; D057225:Data Mining; D030541:Databases, Genetic; D020869:Gene Expression Profiling / Q000379:methods*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005819:Genetic Markers; D006801:Humans; D009432:Neural Crest / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D018570:Risk Assessment; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D005819:Genetic Markers
keywords: Alternative testing; Developmental toxicity; Neural crest cells; Transcriptome profiling