TCDD induced pericardial edema and relative COX-2 expression in medaka (Oryzias latipes) embryos

Exposure to dioxin and other AhR ligands results in multiple, specific developmental cardiovascular phenotypes including pericardial edema and circulatory failure in small aquarium fish models. While 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 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 non-edematous 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 to their non-edematous cohort. AA exposure does not result in significant induction of CYP1A expression suggesting that PE can be induced independent of AhR/ARNT/DRE 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.