Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling

Neurotoxicology. 2015 Sep;50:56-70. doi: 10.1016/j.neuro.2015.07.008. Epub 2015 Jul 31.

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.

Keywords: Chemical grouping; Gene expression; HDAC inhibitors; Metals; Migration; Neural crest; PCBs; Pathways of toxicity; Pesticides; Read-across; Toxicology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Cell Movement / drug effects*
  • Discriminant Analysis
  • Gene Expression Profiling
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hazardous Substances / pharmacology*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Human Embryonic Stem Cells
  • Humans
  • Hydroxamic Acids / pharmacology
  • Neural Crest / drug effects*
  • Oligonucleotide Array Sequence Analysis
  • Time Factors
  • Toxicity Tests
  • Transcription, Genetic / drug effects*
  • Transfection
  • Up-Regulation / drug effects
  • Vorinostat

Substances

  • Hazardous Substances
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Green Fluorescent Proteins
  • trichostatin A
  • Vorinostat