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

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.09.021· OSTI ID:21182689

Teraoka, Hiroki ^[1]; Kubota, Akira ^[1]; Dong, Wu ^[1]; Kawai, Yusuke ^[1]; Yamazaki, Koji; Mori, Chisato ^[2]; Harada, Yoshiteru ^[3]; Peterson, Richard E ^[4]; Hiraga, Takeo ^[1]

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1. Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501 (Japan)
2. Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University, Chiba (Japan)
3. Department of Mediator and Signal Transduction Pharmacology, Kitasato University Graduate School of Medical Sciences, Sagamihara (Japan)
4. School of Pharmacy, University of Wisconsin, Madison, WI (United States)

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.

• OSTI ID: 21182689
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 1 Vol. 234; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOSYNTHESIS
BLOOD FLOW
CARBON MONOXIDE
DIOXIN
EMBRYOS
ENZYMES
FAILURES
GENES
HALOGENATED AROMATIC HYDROCARBONS
HYDROCARBONS
OLIGONUCLEOTIDES
PROSTAGLANDINS
RECEPTORS
TOXICITY
VEINS