A comparative transcriptomic study on the effects of valproic acid on two different hESCs lines in a neural teratogenicity test system

Toxicol Lett. 2014 Nov 18;231(1):38-44. doi: 10.1016/j.toxlet.2014.08.023. Epub 2014 Sep 2.

Abstract

A number of in vitro toxicity assays based on human embryonic stem cells (hESCs) are under development in order to provide alternative methods for the screening of chemicals and drugs and to reduce the number of animals needed for developmental toxicity assessment. The major challenge is to demonstrate the reliability of these in vitro methods by correlating the in vitro produced results to the available in vivo data. In this context transcriptomic approaches associated to toxicogenomic database analysis give the possibility to screen, annotate and cluster high numbers of genes and to identify the molecular changes that univocally mark the toxicity induced processes or are indicative of the early initiating events that lead to cellular toxicity. In this retrospective study we compare microarray transcriptomic data derived from two different hESCs lines (HUES1 and H9) exposed to valproic acid (VA) while applying the same differentiation protocol. We present the results of this comparative analysis in light of the known teratogenic effects of VA. The results show molecular changes in the processes of neural development, neural crest migration, apoptosis and regulation of transcription, indicating a good correspondence with the available in vivo data. We also describe common toxicological signatures and provide an interpretation of the observed qualitative differences referring to known biological features of the two hESCs lines.

Keywords: Embryonic stem cells; In vitro test; Microarray; Teratogenicity; Valproic acid (VA).

Publication types

  • Comparative Study

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cluster Analysis
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / pathology
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation / drug effects
  • Humans
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurogenesis / drug effects
  • Neurogenesis / genetics
  • Oligonucleotide Array Sequence Analysis*
  • Principal Component Analysis
  • Risk Assessment
  • Toxicity Tests / methods*
  • Transcription, Genetic / drug effects*
  • Valproic Acid / toxicity*

Substances

  • Valproic Acid