Protective response of the Ah receptor to ANIT-induced biliary epithelial cell toxicity in see-through medaka.
Protective response of the Ah receptor to ANIT-induced biliary epithelial cell toxicity in see-through medaka.
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Ah 受体对透明青鳉中 ANIT 诱导的胆管上皮细胞毒性的保护性反应。
DOI：
10.1093/toxsci/kfm308
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Hinton,DavidE
中科院分区：
文献类型：
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作者：
Volz,DavidC;Kullman,SethW;Howarth,DeannaL;Hardman,RonC;Hinton,DavidE
芳烃受体（Ah受体或AHR）在非哺乳动物模型，特别是硬骨鱼模型中预防疾病相关疾病的适应性作用尚不清楚。因此，本研究的重点是AHR在medaka胆道上皮细胞毒性反应和肝胆改变中的潜在作用。以胆道毒物α-naphthylisothiocyanate （ANIT）为试剂，暴露透明medaka （STII菌株）96 h，每天通过组织学和超微结构分析以及直接通过活鱼体壁成像对鱼进行评估。Brightfield和透射电镜显示，单剂量ANIT （40 mg/kg）可在初始暴露后6小时特异性诱导胆管前上皮细胞（BPDECs）肿胀和凋亡。在ANIT诱导的BPDEC中毒后，STII medaka的体内成像显示48-72小时内胆囊明显变色。总的来说，这些病理数据表明，ANIT暴露导致急性肝胆改变，持续时间小于96小时。然后，我们测试了AHR在anit诱导的肝胆改变中的潜在作用。总的来说，我们证明了(1)在anti诱导的肝胆损伤过程中，肝脏中短暂的AHR激活和细胞色素P450 1A （CYP1A）诱导发生，(2)AHR激动剂预处理部分保护急性肝胆改变，(3)使用基于荧光素酶的报告基因检测，胆红素弱激活小鼠AHR并结合medaca特异性CYP1A启动子，导致AHR元件驱动转录。鉴于胆汁酸和色素存在于哺乳动物和鱼类的肝脏中，这些研究共同表明，胆汁诱导的AHR激活可能在硬骨鱼和啮齿动物之间是保守的。
The adaptive role of the aryl hydrocarbon receptor (Ah receptor or AHR) in protecting against disease-related conditions remains unclear in nonmammalian models, particularly teleosts. Therefore, this study focused on the potential role of AHR in response to biliary epithelial cell toxicity and hepatobiliary alteration in medaka. See-through medaka (STII strain) were exposed for 96 h using the biliary toxicant α-naphthylisothiocyanate (ANIT) as a reagent, and fish were evaluated daily using histological and ultrastructural analysis, and by imaging directly through the body wall of living fish. Brightfield and transmission electron microscopy showed that a single ANIT dose (40 mg/kg) specifically induced swelling and apoptosis of bile preductular epithelial cells (BPDECs) as early as 6 h after initial exposure. Following ANIT-induced BPDEC toxicity, in vivo imaging of STII medaka showed significant gallbladder discoloration from 48–72 h. Collectively, these pathologic data suggested that ANIT exposure resulted in acute hepatobiliary changes, lasting < 96 h following initial exposure. We then tested the potential role of AHR in response to ANIT-induced hepatobiliary alteration. Overall, we demonstrated that (1) transient AHR activation and cytochrome P450 1A (CYP1A) induction in livers occurred during ANIT-induced hepatobiliary impairment, (2) pretreatment with an AHR agonist partially protected against acute hepatobiliary alteration, and (3) using a luciferase-based reporter assay, the bile pigment bilirubin weakly activated mouse AHR and binding to medaka-specific CYP1A promoter, resulting in AHR element–driven transcription. Given that bile acids and pigments are present in mammalian and fish liver, these studies collectively suggest that bile-induced AHR activation may be conserved between teleosts and rodents.