Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity
Hepatic transcriptomic responses to TCDD in dioxin-sensitive and dioxin-resistant rats during the onset of toxicity
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DOI：
10.1016/j.taap.2010.12.010
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发表时间：
2011-03-01
影响因子：
3.8
通讯作者：
Pohjanvirta, Raimo
中科院分区：
文献类型：
--
作者：
Boutros, Paul C.;Yao, Cindy Q.;Pohjanvirta, Raimo
二恶英同系物2，3，7，8-四氯二苯并对二恶英(TCDD)对啮齿动物具有广泛的毒性作用，这些毒性作用都是由配体依赖的转录因子芳烃受体(AHR)介导的。HAN/Wistar(Kuopio)(H/W)品系对许多TCDD诱导的毒性表现出非凡的抵抗力；>；9600µg/kg对H/W大鼠的LD50高于已知的任何其他野生哺乳动物。我们先前的研究表明，这种耐药性主要是由于H/W大鼠表达了一种变异的AHR亚型，该异构体有很大一部分AHR反式激活域缺失。尽管有这么大的缺失。H/W大鼠对TCDD的影响并不完全抵抗；这些动物中的变种AHR仍然完全有能力上调众所周知的二恶英诱导基因。TCDD敏感大鼠(Long-Evans，L E)和抗性大鼠(H/W)分别给予玉米油(限饲或不限饲)和TCDD 100mgkg/kg灌胃4d或10d。利用微阵列进行肝脏转录图谱分析，并通过对41个基因的RT-PCR分析进行验证。在测试的所有时间点，两个菌株的核心基因集都发生了变化，包括CYP1A1、CYP1A2、CYP1B1、NQO1、Aldh3a1、Tiparp、Exoc3和Inmt。在这个核心之外，菌株在反应的广度上有显著的差异：L-E组的基因改变是H/W大鼠的三倍。10天后，L-E大鼠的几乎所有表达基因都出现了失调，这可能反映了新出现的毒性反应。受饲料限制影响的基因要少得多，这表明在TCDD诱导的变化中，只有一小部分是继发于消瘦综合症的。(C)2010 Elsevier Inc.保留所有权利。
The dioxin congener 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes a wide range of toxic effects in rodent species, all of which are mediated by a ligand-dependent transcription-factor, the aryl hydrocarbon receptor (AHR). The Han/Wistar (Kuopio) (H/W) strain shows exceptional resistance to many TCDD-induced toxicities; the LD50 of > 9600 mu g/kg for H/W rats is higher than for any other wild-type mammal known. We previously showed that this resistance primarily results from H/W rats expressing a variant AHR isoform that has a substantial portion of the AHR transactivation domain deleted. Despite this large deletion. H/W rats are not entirely refractory to the effects of TCDD; the variant AHR in these animals remains fully competent to up-regulate well-known dioxin-inducible genes. TCDD-sensitive (Long-Evans, L-E) and resistant (H/W) rats were treated with either corn-oil (with or without feed-restriction) or 100 mu g/kg TCDD for either four or ten days. Hepatic transcriptional profiling was done using microarrays, and was validated by RT-PCR analysis of 41 genes. A core set of genes was altered in both strains at all time points tested, including CYP1A1, CYP1A2, CYP1B1, Nqo1, Aldh3a1, Tiparp, Exoc3, and Inmt. Outside this core, the strains differed significantly in the breadth of response: three-fold more genes were altered in L-E than H/W rats. At ten days almost all expressed genes were dysregulated in L-E rats, likely reflecting emerging toxic responses. Far fewer genes were affected by feed-restriction, suggesting that only a minority of the TCDD-induced changes are secondary to the wasting syndrome. (C) 2010 Elsevier Inc. All rights reserved.