title: Role of aryl hydrocarbon receptor in mesencephalic circulation failure and apoptosis in zebrafish embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and potent developmental toxicant in various animals, with developing fish being the most sensitive organisms. Although the expression of aryl hydrocarbon receptor (AHR) as well as the partner molecule, AHR nuclear translocator (ARNT) in the brain has been reported, the effect of TCDD on the brain remains to be clarified in detail. Previously, we reported local circulation failure and apoptosis in dorsal midbrain caused by TCDD in developing zebrafish. In the present experiments, we investigated the effects of morpholino antisense oligos against aryl hydrocarbon receptor 2 (zfAHR2) (AHR2-MO) on toxicological endpoints caused by TCDD in developing zebrafish. AHR2-MO but not its negative homologue (4mis-AHR2-MO) improved TCDD-evoked circulation failure in mesencephalic vein and reduced the occurrence of apoptosis in dorsal midbrain, with concomitant inhibition of CYP1A induction in vascular endothelium. Injection of bovine serum albumin (BSA) into the general circulation, followed by immunohistochemistry with anti-BSA, showed that TCDD raised vascular permeability to albumin in dorsal midbrain, which was blocked by AHR2-MO and N-acetlycystein. In the absence of TCDD, development of embryos injected with AHR2-MO appeared normal at least until 60 h after fertilization. It is concluded that AHR2 activation in the vascular endothelium of the zebrafish embryo midbrain is involved in the mesencephalic circulation failure and apoptosis elicited by TCDD. This is the further evidence that vascular endothelium is the target of TCDD in relation to local circulation failure and apoptosis in dorsal midbrain.
authors.affiliation: Department of Toxicology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Japan.
authors.forename: Wu
authors.initials: W
authors.lastname: Dong
authors.forename: Hiroki
authors.initials: H
authors.lastname: Teraoka
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsujimoto
authors.forename: John J
authors.initials: JJ
authors.lastname: Stegeman
authors.forename: Takeo
authors.initials: T
authors.lastname: Hiraga
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001775:Blood Circulation / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D004625:Embryo, Nonmammalian / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008636:Mesencephalon / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D009025:Morpholines; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D014680:Veins / Q000187:drug effects / Q000503:physiopathology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: C474372:AHR2 protein, zebrafish; D009025:Morpholines; D016376:Oligonucleotides, Antisense; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D029961:Zebrafish Proteins; C037574:morpholine