title: Ahr2-dependence of PCB126 effects on the swim bladder in relation to expression of CYP1 and cox-2 genes in developing zebrafish.
abstract: The teleost swim bladder is assumed a homolog of the tetrapod lung. Both swim bladder and lung are developmental targets of persistent aryl hydrocarbon receptor (AHR(2)) agonists; in zebrafish (Danio rerio) the swim bladder fails to inflate with exposure to 3,3',4,4',5-pentachlorobiphenyl (PCB126). The mechanism for this effect is unknown, but studies have suggested roles of cytochrome P450 1 (CYP1) and cyclooxygenase 2 (Cox-2) in some Ahr-mediated developmental effects in zebrafish. We determined relationships between swim bladder inflation and CYP1 and Cox-2 mRNA expression in PCB126-exposed zebrafish embryos. We also examined effects on β-catenin dependent transcription, histological effects, and Ahr2 dependence of the effect of PCB126 on swim bladder using morpholinos targeting ahr2. One-day-old embryos were exposed to waterborne PCB126 or carrier (DMSO) for 24h and then held in clean water until day 4, a normal time for swim bladder inflation. The effects of PCB126 were concentration-dependent with EC(50) values of 1.4 to 2.0 nM for induction of the CYP1s, 3.7 and 5.1 nM (or higher) for cox-2a and cox-2b induction, and 2.5 nM for inhibition of swim bladder inflation. Histological defects included a compaction of the developing bladder. Ahr2-morpholino treatment rescued the effect of PCB126 (5 nM) on swim bladder inflation and blocked induction of CYP1A, cox-2a, and cox-2b. With 2nM PCB126 approximately 30% of eleutheroembryos(3) failed to inflate the swim bladder, but there was no difference in CYP1 or cox-2 mRNA expression between those embryos and embryos showing inflated swim bladder. Our results indicate that PCB126 blocks swim bladder inflation via an Ahr2-mediated mechanism. This mechanism seems independent of CYP1 or cox-2 mRNA induction but may involve abnormal development of swim bladder cells.
authors.affiliation: Dept. of Environmental Toxicology, Evolutionary Biology, Centre, Uppsala University, Norbyvägen 18A, 752 36 Uppsala, Sweden. maria.jonsson@ebc.uu.se
authors.forename: Maria E
authors.initials: ME
authors.lastname: Jönsson
authors.forename: Akira
authors.initials: A
authors.lastname: Kubota
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Timme-Laragy
authors.forename: Bruce
authors.initials: B
authors.lastname: Woodin
authors.forename: John J
authors.initials: JJ
authors.lastname: Stegeman
mesh_terms: D000400:Air Sacs / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian / Q000187:drug effects; D004965:Estrogen Antagonists / Q000633:toxicity*; D005260:Female; D006651:Histocytochemistry; D008297:Male; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000819:agonists / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C474372:AHR2 protein, zebrafish; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins; D051176:beta Catenin; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D051546:Cyclooxygenase 2; C023035:3,4,5,3',4'-pentachlorobiphenyl