Proper regulation of the
aryl hydrocarbon receptor (AHR), 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 (Danio rerio) development results in altered heart morphology and function, culminating in death. 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 h after fertilization (hpf), and the hearts were extracted for microarray analysis at 1, 2, 4, and 12 h after exposure (73, 74, 76, and 84 h postfertilization). The remaining body tissue was also collected at each time for comparison.
TCDD rapidly induced expression in 42 genes within 1 to2hof 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. It is noteworthy that 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 down-regulated 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.