Abstract
The aryl hydrocarbon receptor (AHR) is a conserved ligand-activated transcription factor required for proper vertebrate development and homeostasis. The inappropriate activation of AHR by ubiquitous pollutants can lead to adverse effects on wildlife and human health. The zebrafish is a powerful model system that provides a vertebrate data stream that anchors hypothesis at the genetic and cellular levels to observations at the morphological and behavioral level, in a high-throughput format. In order to investigate the endogenous functions of AHR, we generated an AHR2 (homolog of human AHR)-null zebrafish line (ahr2osu1) using the clustered, regulatory interspaced, short palindromic repeats (CRISPR)-Cas9 precision genome editing method. In zebrafish, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) mediated toxicity requires AHR2. The AHR2-null line was resistant to TCDD-induced toxicity, indicating the line can be used to investigate the biological and toxicological functions of AHR2. The AHR2-null zebrafish exhibited decreased survival and fecundity compared to the wild type line. At 36 weeks, histological evaluations of the AHR2-null ovaries revealed a reduction of mature follicles when compared to wild type ovaries, suggesting AHR2 regulates follicle growth in zebrafish. AHR2-null adults had malformed cranial skeletal bones and severely damaged fins. Our data suggests AHR2 regulates some aspect(s) of neuromuscular and/or sensory system development, with impaired behavioral responses observed in larval and adult AHR2-null zebrafish. This study increases our understanding of the endogenous functions of AHR, which may help foster a better understanding of the target organs and molecular mechanisms involved in AHR-mediated toxicities.
Highlights
The aryl hydrocarbon receptor (AHR) is highly conserved across multiple animal phyla and is present throughout metazoans [1]
We identified a founder with an 11 nt deletion that resulted in a premature stop codon upstream of the nuclear localization and export signals, and the bHLH, PAS, and transactivation domains (Fig 1)
Understanding the AHRs fundamental roles in biology may foster a better understanding of the target organs and molecular mechanisms by which inappropriate AHR activation leads to toxicity
Summary
The aryl hydrocarbon receptor (AHR) is highly conserved across multiple animal phyla and is present throughout metazoans [1]. AHR is a ligand-activated member of the basic helix-loophelix PER-ARNT-SIM (bHLH/PAS) protein family of transcription factors [2, 3]. AHR was originally identified for its role in xenobiotic metabolism and severe toxicity of chlorinated. Zebrafish AHR2 required for proper development and analysis, decision to publish, or preparation of the manuscript
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