title: Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling.
abstract: Functional assays, such as the "migration inhibition of neural crest cells" (MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analyzed transcripts of 35 'migration genes' after treatment with 16 migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds.
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dreser
authors.affiliation: Center for Stem Cell Biology, Sloan-Kettering Institute, New York City, NY, USA; Developmental Biology Program, Sloan-Kettering Institute, New York City, NY, USA. Electronic address: bastian.zimmer@uni-konstanz.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Zimmer
authors.affiliation: Lehrstuhl für Bioinformatik und Information Mining, University of Konstanz, Konstanz, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dietz
authors.affiliation: Institute of Computer Science, University of Tartu, Tartu, Estonia.
authors.forename: Elena
authors.initials: E
authors.lastname: Sügis
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pallocca
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Nyffeler
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany; Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Meisig
authors.affiliation: Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany; Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Blüthgen
authors.affiliation: Lehrstuhl für Bioinformatik und Information Mining, University of Konstanz, Konstanz, Germany.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Berthold
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Waldmann
authors.affiliation: Doerenkamp-Zbinden Chair of In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
mesh_terms: D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects*; D016002:Discriminant Analysis; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D015386:Hazardous Substances / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D000066449:Human Embryonic Stem Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009432:Neural Crest / Q000187:drug effects*; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors; D018675:Toxicity Tests; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D015386:Hazardous Substances; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D000077337:Vorinostat
keywords: Chemical grouping; Gene expression; HDAC inhibitors; Metals; Migration; Neural crest; PCBs; Pathways of toxicity; Pesticides; Read-across; Toxicology