| Role of the cyclooxygenase 2-thromboxane pathway in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced decrease in mesencephalic vein blood flow in the zebrafish embryo. | |
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MedLine Citation:
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PMID: 18952116 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Previously, we reported that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) evoked developmental toxicity required activation of aryl hydrocarbon receptor type 2 (AHR2), using zebrafish embryos. However, the downstream molecular targets of AHR2 activation are largely unknown and are the focus of the present investigation. TCDD induces cyclooxygenase 2 (COX2), a rate-limiting enzyme for prostaglandin synthesis in certain cells. In the present study, we investigated the role of the COX2-thromboxane pathway in causing a specific endpoint of TCDD developmental toxicity in the zebrafish embryo, namely, a decrease in regional blood flow in the dorsal midbrain. It was found that the TCDD-induced reduction in mesencephalic vein blood flow was markedly inhibited by selective COX2 inhibitors, NS-398 and SC-236, and by a general COX inhibitor, indomethacin, but not by a selective COX1 inhibitor, SC-560. Gene knock-down of COX2 by two different types of morpholino antisense oligonucleotides, but not by their negative homologs, also protected the zebrafish embryos from mesencephalic vein circulation failure caused by TCDD. This inhibitory effect of TCDD on regional blood flow in the dorsal midbrain was also blocked by selective antagonists of the thromboxane receptor (TP). Treatment of control zebrafish embryos with a TP agonist also caused a reduction in mesencephalic vein blood flow and it too was blocked by a TP antagonist, without any effect on trunk circulation. Finally, gene knock-down of thromboxane A synthase 1 (TBXS) with morpholinos but not by the morpholinos' negative homologs provided significant protection against TCDD-induced mesencephalic circulation failure. Taken together, these results point to a role of the prostanoid synthesis pathway via COX2-TBXS-TP in the local circulation failure induced by TCDD in the dorsal midbrain of the zebrafish embryo. |
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Authors:
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Hiroki Teraoka; Akira Kubota; Wu Dong; Yusuke Kawai; Koji Yamazaki; Chisato Mori; Yoshiteru Harada; Richard E Peterson; Takeo Hiraga |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-10-08 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 234 ISSN: 1096-0333 ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-16 Completed Date: 2009-01-09 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 33-40 Citation Subset: IM |
Affiliation:
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Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan. hteraoka@rakuno.ac.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cyclooxygenase 2 / drug effects*, metabolism Embryo, Nonmammalian / drug effects Environmental Pollutants / toxicity* Enzyme Induction / drug effects* Mesencephalon / blood supply, drug effects* Prostaglandins / biosynthesis Receptors, Thromboxane Regional Blood Flow / drug effects Tetrachlorodibenzodioxin / toxicity* Thromboxane-A Synthase / drug effects, metabolism Zebrafish / embryology, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Environmental Pollutants; 0/Prostaglandins; 0/Receptors, Thromboxane; 1746-01-6/Tetrachlorodibenzodioxin; EC 1.14.99.1/Cyclooxygenase 2; EC 5.3.99.5/Thromboxane-A Synthase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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