title: TCDD induced pericardial edema and relative COX-2 expression in medaka (Oryzias Latipes) embryos.
abstract: Exposure to dioxin and other aryl hydrocarbon receptor (AhR) ligands results in multiple, specific developmental cardiovascular phenotypes including pericardial edema and circulatory failure in small aquarium fish models. Although phenotypes are well described, mechanistic underpinnings for such toxicities remain elusive. Here we suggest that AhR activation results in stimulation of inflammation and "eicosanoid" pathways, which contribute to the observed developmental, cardiovascular phenotypes. We demonstrate that medaka embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (0.05-1 ppb) during early development result in a dose-related increase in the prevalence of pericardial edema and that this phenotype correlates with an increase in cyclooxygenase-2 (COX-2) gene expression. Those individuals exhibiting the edema phenotype had significantly greater COX-2 mRNA than their nonedematous cohort. Selective pharmacological inhibition of COX-2, with NS-398, and genetic knock down of COX-2 with a translation initiation morpholino significantly attenuated prevalence and severity of edema phenotype. Subsequently, exposures of medaka embryos to arachidonic acid (AA) resulted in recapitulation of the pericardial edema phenotype and significantly increased COX-2 expression only in those individuals exhibiting the edema phenotype compared with their nonedematous cohort. AA exposure does not result in significant induction of cytochrome P450 1A expression, suggesting that pericardial edema can be induced independent of AhR/aryl hydrocarbon receptor nuclear translocator/dioxin response element interactions. Results from this study demonstrate that developmental exposure to TCDD results in an induction of inflammatory mediators including COX-2, which contribute to the onset, and progression of heart dysmorphogenesis in the medaka model.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695, USA.
authors.forename: Wu
authors.initials: W
authors.lastname: Dong
authors.forename: Fumio
authors.initials: F
authors.lastname: Matsumura
authors.forename: Seth W
authors.initials: SW
authors.lastname: Kullman
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects* / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020868:Gene Silencing; D009578:Nitrobenzenes / Q000494:pharmacology; D009990:Oryzias / Q000502:physiology*; D010490:Pericardial Effusion / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013723:Teratogens / Q000633:toxicity*
chemical_list: D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D013449:Sulfonamides; D013723:Teratogens; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2
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