Prostanoid Signaling Mediates Circulation Failure Caused by TCDD in Developing Zebrafish

Using zebrafish embryos, we reported that 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) evoked circulation failure through activation of the aryl hydrocarbon receptor type 2 (AHR2). However, the following molecular target after AHR2 activation is largely unclear. It has been reported that TCDD induces cyclooxygenase 2 (COX2), a rate-limiting enzyme for prostaglandin synthesis in some cells. In this study, we investigated the involvement of cyclooxygenase on developmental toxicity in zebrafish exposed to TCDD. TCDD-induced mesencephalic circulation failure was markedly inhibited by selective COX2 inhibitors and by a general COX inhibitor, but not by a selective COX1 inhibitor. Gene knock-down of COX2 by morpholino antisense oligo nucleotides also recovered mesencephalic circulation failure by TCDD. The effect of TCDD was also blocked by selective antagonists for thromboxane receptor (TP). Conversely, TP agonist induced mesencephalic circulation failure, which was abolished by TP antagonist, without any effect on trunk circulation. Furthermore, gene knock-down of thromboxane A synthase 1 (TBXS) with morpholinos significantly inhibited TCDD-induced mesencephalic circulation failure. Overall similar results with selective chemicals on prostaglandin signaling were obtained for pericardial edema by TCDD. These results suggest the involvement of prostanoid synthesis pathway by way of COX2-TBXS-TP in TCDD-induced local circulation failure in developing zebrafish.