Comparative genomics identifies genes mediating cardiotoxicity in the embryonic zebrafish heart

Physiol Genomics. 2008 Apr 22;33(2):148-58. doi: 10.1152/physiolgenomics.00214.2007. Epub 2008 Jan 29.


Retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activate distinct ligand-dependent transcription factors, and both cause cardiac malformation and heart failure in zebrafish embryos. We hypothesized that they cause this response by hyperactivating a common set of genes critical for heart development. To test this, we used microarrays to measure transcript changes in hearts isolated from zebrafish embryos 1, 2, 4, and 12 h after exposure to 1 muM RA. We used hierarchical clustering to compare the transcriptional responses produced in the embryonic heart by RA and TCDD. We could identify no early responses in common between the two agents. However, at 12 h both treatments produced a dramatic downregulation of a common cluster of cell cycle progression genes, which we term the cell cycle gene cluster. This was associated with a halt in heart growth. These results suggest that RA and TCDD ultimately trigger a common transcriptional response associated with heart failure, but not through the direct activation of a common set of genes. Among the genes rapidly induced by RA was Nr2F5, a member of the COUP-TF family of transcriptional repressors. We found that induction of Nr2F5 was both necessary and sufficient for the cardiotoxic response to RA.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cardiotoxins / toxicity*
  • Cell Count
  • Edema / genetics
  • Embryo, Nonmammalian / drug effects*
  • Embryo, Nonmammalian / metabolism
  • Fertilization / drug effects
  • Gene Expression Regulation, Developmental / drug effects
  • Genomics*
  • Heart / drug effects*
  • Heart / embryology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / pathology
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense / pharmacology
  • Polychlorinated Dibenzodioxins / toxicity
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reproducibility of Results
  • Time Factors
  • Tretinoin / toxicity
  • Zebrafish / embryology*
  • Zebrafish / genetics*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism


  • Cardiotoxins
  • Oligonucleotides, Antisense
  • Polychlorinated Dibenzodioxins
  • RNA, Messenger
  • Zebrafish Proteins
  • Tretinoin