A chimeric aryl hydrocarbon receptor knockout mouse model indicates that aryl hydrocarbon receptor activation in hematopoietic cells contributes to the hepatic lesions induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin.
A chimeric aryl hydrocarbon receptor knockout mouse model indicates that aryl hydrocarbon receptor activation in hematopoietic cells contributes to the hepatic lesions induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin.
复制标题
嵌合芳烃受体敲除小鼠模型表明，造血细胞中芳烃受体的激活导致2,3,7,8-四氯二苯并-对二恶英诱导的肝脏损伤。
DOI：
10.1006/taap.1999.8681
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发表时间：
1999
影响因子：
3.8
通讯作者：
Gasiewicz,TA
中科院分区：
文献类型：
--
作者：
Thurmond,TS;Silverstone,AE;Baggs,RB;Quimby,FW;Staples,JE;Gasiewicz,TA
据报道，在许多物种的肝脏中，与2，3，7，8-四氯二苯并对二恶英（TCDD）接触相关的病理变化。虽然这些变化已被广泛描述，但产生这些病变的毒性相互作用机制仍不清楚。使用芳烃受体（Ahr）敲除雄性小鼠嵌合模型，我们研究了这种受体在造血和/或实质细胞中的存在是否会影响TCDD诱导的肝毒性。骨髓嵌合体是通过辐射小鼠的造血重建产生的。具体而言，用芳香烃受体（AHR）阳性造血和实质细胞（Ahr+/+动物骨髓细胞转化为辐照Ahr+/+动物）、AHR阳性造血和阴性实质细胞（Ahr+/+转化为Ahr−/−）、AHR阴性造血和阳性实质细胞（Ahr−/−转化为Ahr+/+）以及AHR阴性造血和实质细胞（Ahr−/−转化为Ahr−/−）生成嵌合体。雄性野生型（Ahr+/+）和敲除（Ahr−/−）动物用作非嵌合对照。在TCDD处理（30 μg/kg体重）后，对每个对照组和嵌合组小鼠的肝脏切片进行组织学评价，以观察坏死和炎症变化。TCDD处理在Ahr+/+对照中产生中度炎症，而在Ahr+/+嵌合体中产生中度炎症。在TCDD处理的Ahr−/−、Ahr−/−转化为Ahr−/−、Ahr+/+转化为Ahr−/−和Ahr−/−转化为Ahr+/+动物中，这种反应是轻度的，与相应的溶剂处理组没有差异。在所有TCDD治疗的对照组或AHR阳性实质的嵌合体中观察到中度坏死。在TCDD和溶剂处理的动物中没有观察到或观察到轻度坏死，其中含有AHR阴性实质。这些数据表明，肝实质中的AHR单独存在是足够的TCDD诱导肝坏死，其存在于造血细胞是必要的TCDD诱导的肝损伤的炎症反应。
Pathologic changes associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure have been reported in the livers of a wide range of species. While these changes have been extensively described, the mechanisms of toxic interaction(s) that produce these lesions remain unclear. Using an aryl hydrocarbon receptor (Ahr) knockout male mouse chimeric model, we investigated whether the presence of this receptor in hematopoietic and/or parenchymal cells affects TCDD-induced hepatotoxicity. Bone marrow chimeras were produced by hematopoietic reconstitution of irradiated mice. Specifically, chimeras were generated with aryl hydrocarbon receptor (AHR) positive hematopoietic and parenchymal cells (Ahr+/+animal bone marrow cells into irradiated Ahr+/+animals), AHR positive hematopoietic and negative parenchymal cells (Ahr+/+into Ahr−/−), AHR negative hematopoietic and positive parenchymal cells (Ahr−/−into Ahr+/+), and AHR negative hematopoietic and parenchymal cells (Ahr−/−into Ahr−/−). Male wild-type (Ahr+/+) and knockout (Ahr−/−) animals were used as nonchimeric controls. Following TCDD treatment (30 μg/kg body wt), liver sections from mice in each control and chimeric group were histologically evaluated for necrotic and inflammatory changes. TCDD treatment produced moderate inflammation in Ahr+/+controls and Ahr+/+into Ahr+/+chimeras. This response was mild in TCDD-treated Ahr−/−, Ahr−/−into Ahr−/−, Ahr+/+into Ahr−/−, and Ahr−/−into Ahr+/+animals and was not different from the corresponding vehicle-treated groups. Moderate necrosis was observed in all TCDD-treated controls or chimeras with AHR-positive parenchyma. No or mild necrosis was observed in TCDD- and vehicle-treated animals containing AHR-negative parenchyma. These data indicate that the presence of AHR in hepatic parenchyma alone is sufficient for TCDD induction of hepatic necrosis, and its presence in hematopoietic cells is necessary for the inflammatory response to TCDD-induced hepatic lesions.