title: Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish.
abstract: The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration-response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b-thromboxane pathway in precardiac edema formation following TCDD exposure in developing zebrafish.
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan. Electronic address: hteraoka@rakuno.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Teraoka
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nijoukubo
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yamakoshi
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison, WI, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
authors.affiliation: Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Stegeman
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Takio
authors.initials: T
authors.lastname: Kitazawa
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Hiraga
authors.affiliation: School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan; Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Kubota
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004489:Edema, Cardiac / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013931:Thromboxanes / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C474372:AHR2 protein, zebrafish; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D013931:Thromboxanes; D014874:Water Pollutants, Chemical; D029961:Zebrafish Proteins; C000630526:arnt protein, zebrafish; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051546:Cyclooxygenase 2; D001205:Ascorbic Acid
keywords: Cyclooxygenase; Danio rerio; Developmental toxicology; Edema; TCDD; Thromboxane