Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms
Retinoid status and responsiveness to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking retinoid binding protein or retinoid receptor forms
复制标题
DOI：
10.1016/j.cbi.2005.06.006
复制
发表时间：
2005-09-10
影响因子：
5.1
通讯作者：
Håkansson, H
中科院分区：
文献类型：
--
作者：
Hoegberg, P;Schmidt, CK;Håkansson, H
我们研究了维生素A（类维生素A）蛋白在正常条件下和由2，3，7，8-四氯二苯并-p-二恶英（TCDD）诱导的化学应激过程中在肝脏类维生素A加工中的作用，TCDD是一种已知会干扰类维生素A周转和代谢的化学物质。在野生型对照小鼠和缺乏维甲酸受体（RAR）、类维生素A X受体（RXR）或细胞内类维生素A结合蛋白（CRABP I、CRABP II、CRBP I）的一种或多种亚型的转基因小鼠中进行了三项单独的研究。从2周龄至成年监测体重和器官重量发育，并研究视黄酯、视黄醇和视黄酸的肝脏水平。此外，还测定了9-顺式-4-氧代-13，14-二氢视黄酸的肝脏浓度，视黄酸是最近发现的一种类维生素A代谢物，已被证明对TCDD暴露和维生素A状态敏感。与野生型小鼠相比，三种蛋白CRBP I、CRABP I和CRABP II（CI/CAI/CAII（-/-））缺失的小鼠显示出显著较低的肝脏视黄酯、视黄醇和全反式视黄酸水平，而9-顺式-4-氧代-13，14-二氢视黄酸的肝脏浓度显著较高。用TCDD处理后，CI/CAI/CAII（-/-）小鼠的肝脏总类维生素A几乎完全耗尽，而野生型小鼠和缺乏CRABP I和CRABP II（CAI/CAII（-/-））的小鼠在28天时与对照组相比保留了约60-70%的维生素A含量。RAR和RXR基因敲除小鼠对TCDC诱导的类维生素A破坏的反应与野生型小鼠相似，但RXR β（-/-）小鼠除外，其肝脏维生素A浓度没有下降，这表明RXR β在TCDC诱导的类维生素A破坏中的作用应进一步研究。总的来说，在三基因敲除小鼠（CI/CAI/CAII（-/-））中，而不是在双基因敲除小鼠（CAI/CAII（-/-））中，异常的类维生素A谱表明CRBP I的缺失可能是CI/CAI/CAII（-/-）小鼠中类维生素A谱差异的原因，并且可能导致二恶英暴露后对肝脏类维生素A耗竭的敏感性增加。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
We have investigated the role of Vitamin A (retinoid) proteins in hepatic retinoid processing under normal conditions and during chemical stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a chemical known to interfere with retinoid turnover and metabolism. Three separate studies were performed in wildtype control mice and transgenic mice that lack one or more isoforms of retinoic acid receptors (RAR), retinoid X receptors (RXR), or intracellular retinoid-binding proteins (CRABP I, CRABP II, CRBP I). Body and organ weight development was monitored from 2 weeks of age to adult, and hepatic levels of retinyl esters, retinol, and retinoic acid were investigated. In addition, hepatic concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid, a recently discovered retinoid metabolite that has proven sensitive to both TCDD exposure and Vitamin A status, were also determined. Mice absent in the three proteins CRBP I, CRABP I, and CRABP II (CI/CAI/CAII(-/-)) displayed significantly lower hepatic retinyl ester, retinol, and all-trans-retinoic acid levels compared to wildtype mice, whereas the liver concentrations of 9-cis-4-oxo-13,14-dihydro-retinoic acid was considerably higher. After treatment with TCDD, hepatic total retinoids were almost entirely depleted in the CI/CAI/CAII(-/-) mice, whereas wildtype mice and mice lacking CRABP I, and CRABP II (CAI/CAII(-/-)) retained approximately 60-70% of their Vitamin A content compared to controls at 28 days. RAR and RXR knockout mice responded similarly to wildtype mice with respect to TCDD-induced retinoid disruption, with the exception of RXR beta(-/-) mice which showed no decrease in hepatic Vitamin A concentration, suggesting that the role of RXR beta in TCDD-induced retinoid disruption should be further investigated. Overall, the abnormal retinoid profile in the triple knockout mice (CI/CAI/CAII(-/-)), but not double knockout (CAI/CAII(-/-)) mice, suggests that a loss of CRBP I may account for the difference in retinoid profile in CI/CAI/CAII(-/-) mice, and is likely to result in an increased susceptibility to hepatic retinoid depletion following dioxin exposure. (c) 2005 Elsevier Ireland Ltd. All rights reserved.