Aryl hydrocarbon receptor activation produces heart-specific transcriptional and toxic responses in developing zebrafish
- Carney, S.A., Chen, J., Burns, C.G., Xiong, K.M., Peterson, R.E., and Heideman, W.
- Molecular pharmacology 70(2): 549-561 (Journal)
- Registered Authors
- Burns, Geoff, Carney, Sara A., Chen, Jing, Heideman, Warren, Peterson, Richard E., Xiong, Kong M.
- Pharmacogenomic analyses, Fluorescence techniques, Regulation of gene expression, Regulation-transcriptional, Ah receptor, Toxicant-induced gene express
- MeSH Terms
- Aryl Hydrocarbon Receptor Nuclear Translocator/physiology
- Gene Expression Profiling
- Heart/drug effects*
- Oligonucleotide Array Sequence Analysis
- Receptors, Aryl Hydrocarbon/physiology*
- Research Design
- Transcription, Genetic/drug effects*
- 16714409 Full text @ Mol. Pharmacol.
Carney, S.A., Chen, J., Burns, C.G., Xiong, K.M., Peterson, R.E., and Heideman, W. (2006) Aryl hydrocarbon receptor activation produces heart-specific transcriptional and toxic responses in developing zebrafish. Molecular pharmacology. 70(2):549-561.
Proper regulation of the aryl hydrocarbon receptor, a ligand activated transcription factor, is required for normal vertebrate cardiovascular development. AHR hyperactivation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during zebrafish development results in altered heart morphology and function culminating in mortality. To identify genes that may cause cardiac toxicity, we analyzed the transcriptional response to TCDD in zebrafish hearts. Zebrafish larvae were exposed to TCDD for 1 h at 72 hpf, and the hearts were extracted for microarray analysis at 1, 2, 4 and 12 h after exposure (73, 74, 76 and 84 hpf). The remaining body tissue was also collected at each time for comparison. TCDD rapidly induced expression in 42 genes within 1 - 2 h of exposure. These genes function in xenobiotic metabolism, proliferation, heart contractility, and pathways that regulate heart development. Furthermore, these expression changes preceded signs of cardiovascular toxicity, characterized by decreased stroke volume, peripheral blood flow, and a halt in heart growth. This identifies strong candidates for important AHR target genes. Interestingly, the TCDD-induced transcriptional response in the hearts of zebrafish larvae was substantially different from that induced in the rest of the body tissues. One of the biggest differences included a cluster of genes that were downregulated 12 h after exposure in heart tissue, but not in the body samples. More than 70% of the transcripts in this heart-specific cluster promote cellular growth and proliferation. Thus, the developing heart stands out as being responsive to TCDD at both the level of toxicity and gene expression.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes