Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity
Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity
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DOI：
10.1006/taap.1996.0210
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发表时间：
1996-09-01
影响因子：
3.8
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
FernandezSalguero, PM;Hilbert, DM;Gonzalez, FJ
哺乳动物急性暴露于环境污染物 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 会导致多种毒理学和病理效应。其中一些效应的机制已在体外进行了广泛研究，相关研究表明芳烃受体 (AHR) 转录因子参与其中。然而，由于效应的多样性和该受体的普遍表达，很难确定 AHR 与 TCDD 介导的毒性之间的明确关联。为了区分 AHR 介导的 TCDD 毒性与替代途径产生的毒性，我们利用了最近描述的 AHR 缺陷小鼠，该小鼠是通过胚胎干细胞中位点特异性同源重组产生的。目前的研究表明，AHR 缺陷小鼠相对不受 TCDD 剂量（2000 μg/kg）的影响，TCDD 剂量比在表达功能性 AHR 的同窝小鼠中引起严重毒性和病理效应的剂量高 10 倍。对 AHR 缺陷小鼠的肝脏、胸腺、心脏、肾脏、胰腺、脾脏、淋巴结和子宫的分析未发现明显的 TCDD 诱导的病变。 AHR 缺陷小鼠对 TCDD 诱导的胸腺萎缩的抵抗似乎仅限于涉及 AHR 的过程，因为皮质类固醇地塞米松在 AHR 缺陷和正常同窝对照小鼠中快速有效地诱导皮质耗竭。综上所述，这些结果表明 TCDD 在肝脏和胸腺中诱导的病理变化完全由 AHR 介导。然而，值得注意的是，在高剂量的 TCDD 下，AHR 缺陷小鼠的肺和肝脏分别表现出有限的血管炎和散在的单细胞坏死。负责这些明显与受体无关的过程的机制仍不清楚，但可能涉及 TCDD 诱导毒性的新的替代途径。 (C) 1996 学术出版社
Acute exposure of mammals to the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a diverse set of toxicologic and pathologic effects. The mechanism of some of these effects has been studied extensively in vitro and correlative studies have indicated the involvement of a transcription factor known as the aryl hydrocarbon receptor (AHR), However, a definitive association of the AHR with TCDD-mediated toxicity has been difficult to establish due to the diversity of effects and the ubiquitous expression of this receptor. In an effort to distinguish AHR-mediated TCDD toxicities from those resulting from alternative pathways, we have made use of the recently described AHR-deficient mouse that was generated by locus-specific homologous recombination in embryonic stem cells. Present studies demonstrate that AHR-deficient mice are relatively unaffected by doses of TCDD (2000 mu g/kg) 10-fold higher than that found to induce severe toxic and pathologic effects in littermates expressing a functional AHR, Analyses of liver, thymus, heart, kidney, pancreas, spleen, lymph nodes, and uterus from AHR-deficient mice identified no significant TCDD-induced lesions. The resistance of AHR-deficient mice to TCDD-induced thymic atrophy appears restricted to processes involving AHR since the corticosteroid dexamethasone rapidly and efficiently induced cortical depletion in both AHR-deficient and normal littermate control mice, Taken together these results suggest that the pathological changes induced by TCDD in the liver and thymus are mediated entirely by the AHR. However, it is important to note that at high doses of TCDD, AHR-deficient mice displayed limited vasculitis and scattered single cell necrosis in their lungs and livers, respectively. The mechanism(s) responsible for these apparently receptor-independent processes remain unclear but may involve novel, alternative pathways for TCDD-induced toxicity. (C) 1996 Academic Press, Inc.