ahr2 mutant reveals functional diversity of aryl hydrocarbon receptors in zebrafishahr2变异显示功能的多样性芳基碳氢化合物在斑马鱼受体.pdfVIP

AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish 1 1 2 3 3 Britton C. Goodale , Jane K. La Du , William H. Bisson , Derek B. Janszen , Katrina M. Waters , Robert L. Tanguay1* 1 Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America, 2 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland, 3 Computational Biology and Bioinformatics Group, Pacific Northwest National Laboratory, Richland, Washington, United States of America Abstract The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non- functional pse