Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish.
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.
['Teraoka|Hiroki|H|', 'Okuno|Yuki|Y|', 'Nijoukubo|Daisuke|D|', 'Yamakoshi|Ayumi|A|', 'Peterson|Richard E|RE|', 'Stegeman|John J|JJ|', 'Kitazawa|Takio|T|', 'Hiraga|Takeo|T|', 'Kubota|Akira|A|']
D000818:Animals D000975:Antioxidants D051784:Aryl Hydrocarbon Receptor Nuclear Translocator D001205:Ascorbic Acid D051546:Cyclooxygenase 2 D052246:Cyclooxygenase 2 Inhibitors D004489:Edema, Cardiac D004625:Embryo, Nonmammalian D015971:Gene Expression Regulation, Enzymologic D055785:Gene Knockdown Techniques D000072317:Polychlorinated Dibenzodioxins D018336:Receptors, Aryl Hydrocarbon D015398:Signal Transduction D013931:Thromboxanes D014874:Water Pollutants, Chemical D015027:Zebrafish D029961:Zebrafish Proteins
Edema TCDD Cyclooxygenase Thromboxane Danio rerio Developmental toxicology