Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance
Differential expression profiling of the hepatic proteome in a rat model of dioxin resistance
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DOI：
10.1074/mcp.m500415-mcp200
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发表时间：
2006-05-01
影响因子：
7
通讯作者：
Fanelli, R
中科院分区：
文献类型：
--
作者：
Pastorelli, R;Carpi, D;Fanelli, R
急性 2,3,7,8-四氯二苯并二恶英 (TCDD) 毒性的一个特征是种间和品系间敏感性的显着差异。这使得人类二恶英风险评估变得复杂。然而，这种变异性也提供了一种表征二恶英毒性机制的方法。 Long-Evans (Turku/AB) 大鼠比 Han/Wistar (Kuopio) 大鼠更容易受到 TCDD 致死性的影响，这种差异构成了识别二恶英毒性机制的非常有用的模型。我们采用蛋白质组学方法来鉴定 TCDD 暴露对 Han/Wistar 大鼠与 Long-Evans 大鼠肝脏蛋白表达的差异影响。这允许确定哪些蛋白质标记物（如果有的话）指示二恶英敏感性差异和/或负责赋予抗性。使用二维凝胶电泳、计算机凝胶图像分析、凝胶内消化和质谱法评估总肝蛋白中的差异蛋白表达。我们观察到几种蛋白质丰度的显着变化，这些蛋白质分为三类：（i）不依赖于 TCDD 且完全具有菌株特异性（例如蛋白质二硫键异构酶 A3、雷古钙素和胍丁胺尿素水解酶的亚型）； (ii) 与菌株无关且仅依赖于 TCDD 暴露（例如乙醛脱氢酶 3A1 和大鼠硒结合蛋白 2）； (iii) 取决于 TCDD 暴露和应变（例如氧化应激相关蛋白、凋亡诱导因子和 MAWD 结合蛋白）。通过整合转录组（微阵列）数据和基因组数据（调控元件的计算搜索），我们发现蛋白质表达水平主要控制在转录水平。这些结果首次揭示了肝蛋白的一个子集，它们以菌株特异性方式对 TCDD 做出差异性调节。其中一些差异反应可能在确定这两种大鼠品系之间 TCDD 反应的主要差异方面发挥了作用。因此，我们的工作有望对 TCDD 毒性和耐药机制产生新的见解。
One characteristic feature of acute 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) toxicity is dramatic interspecies and interstrain variability in sensitivity. This complicates dioxin risk assessment for humans. However, this variability also provides a means of characterizing mechanisms of dioxin toxicity. Long-Evans (Turku/AB) rats are orders of magnitude more susceptible to TCDD lethality than Han/Wistar (Kuopio) rats, and this difference constitutes a very useful model for identifying mechanisms of dioxin toxicity. We adopted a proteomic approach to identify the differential effects of TCDD exposure on liver protein expression in Han/Wistar rats as compared with Long-Evans rats. This allows determination of which, if any, protein markers are indicative of differences in dioxin susceptibility and/or responsible for conferring resistance. Differential protein expression in total liver protein was assessed using two-dimensional gel electrophoresis, computerized gel image analysis, in-gel digestion, and mass spectrometry. We observed significant changes in the abundance of several proteins, which fall into three general classes: (i) TCDD-independent and exclusively strain-specific (e. g. isoforms of the protein-disulfide isomerase A3, regucalcin, and agmatine ureohydrolase); (ii) strain-independent and only dependent on TCDD exposure (e. g. aldehyde dehydrogenase 3A1 and rat selenium-binding protein 2); (iii) dependent on both TCDD exposure and strain (e. g. oxidative stress-related proteins, apoptosis-inducing factor, and MAWD-binding protein). By integrating transcriptomic (microarray) data and genomic data (computational search of regulatory elements), we found that protein expression levels were mainly controlled at the level of transcription. These results reveal, for the first time, a subset of hepatic proteins that are differentially regulated in response to TCDD in a strain-specific manner. Some of these differential responses may play a role in establishing the major differences in TCDD response between these two strains of rats. As such, our work is expected to lead to new insights into the mechanism of TCDD toxicity and resistance.