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Aryl Hydrocarbon Receptor Activation Produces Heart-Specific Transcriptional and Toxic Responses in Developing Zebrafish

Molecular and Environmental Toxicology Program (S.A.C., R.E.P., W.H.), Pharmaceutical Sciences (J.C., R.E.P., W.H.), and Biomolecular Chemistry (K.M.X., W.H.), University of Wisconsin, Madison, Wisconsin; and Cardiovascular Research Center, Massachusetts General Hospital, Harvard University, Charlestown, Massachusetts (C.G.B.)

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.

Address correspondence to: Warren Heideman, University of Wisconsin-Madison, School of Pharmacy, 5111 Rennebohm Hall, 777 Highland Avenue, Madison, WI 53705. E-mail: wheidema{at}wisc.edu

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