TCDD Induced Pericardial Edema and Relative COX-2 Expression in Medaka (Oryzias Latipes) Embryos
TCDD Induced Pericardial Edema and Relative COX-2 Expression in Medaka (Oryzias Latipes) Embryos
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DOI：
10.1093/toxsci/kfq254
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发表时间：
2010-11-01
影响因子：
3.8
通讯作者：
Kullman, Seth W.
中科院分区：
文献类型：
--
作者：
Dong, Wu;Matsumura, Fumio;Kullman, Seth W.
在小型观赏鱼模型中，暴露于二恶英和其他芳烃受体（AhR）配体会导致多种特定的发育性心血管表型，包括心包水肿和循环衰竭。虽然表型描述得很好，但这种毒性的机制基础仍然难以捉摸。在这里，我们认为AhR激活导致炎症和“类二十烷”途径的刺激，这有助于观察到的发育和心血管表型。我们证明，在发育早期暴露于2,3,7,8-四氯二苯并-对二恶英（TCDD） （0.05-1 ppb）的medaka胚胎会导致心包水肿发生率的剂量相关增加，并且这种表型与环氧化酶-2 （COX-2）基因表达的增加相关。那些表现出水肿表型的个体的COX-2 mRNA明显高于非水肿组。用NS-398选择性药理抑制COX-2，以及用翻译起始morpholino基因敲低COX-2，可显著降低水肿表型的患病率和严重程度。随后，将medaka胚胎暴露于花生四烯酸（AA）中导致心包水肿表型重现，并且仅在那些表现出水肿表型的个体中，COX-2表达显著增加。AA暴露不显著诱导细胞色素P450 1A表达，提示心包水肿可独立于AhR/芳烃受体核转运子/二恶英反应元件相互作用诱导。本研究的结果表明，在发育过程中暴露于TCDD会导致包括COX-2在内的炎症介质的诱导，这有助于medaka模型中心脏畸形的发生和进展。
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.