Methapyrilene toxicity: Anchorage of pathologic observations to gene expression alterations
Methapyrilene toxicity: Anchorage of pathologic observations to gene expression alterations
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DOI：
10.1080/01926230290105712
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发表时间：
2002-07-01
影响因子：
1.5
通讯作者：
Paules, RS
中科院分区：
文献类型：
--
作者：
Hamadeh, HK;Knight, BL;Paules, RS
甲基吡喃(MP)暴露于动物体内可引起包括肝毒性在内的一系列不良病理反应。本研究研究MP治疗后的基因表达和组织病理学改变，目的是1)利用计算方法根据MP治疗大鼠相应组织中毒性的严重程度对来自肝脏的样本进行分类，2)表型锚定基因表达模式，以及3)深入了解甲基苯丙胺肝毒性的机制(S)。监测了雄性SD大鼠在每日剂量为10或100 mg/kg/d后暴露于啮齿动物肝癌物质MP 1、3或7天后的大规模差异基因表达水平。等级聚类和主成分分析成功地将样本分类，与显微镜观察一致，并揭示了组织病理学没有观察到的低剂量效应。来自基因芯片分析的数据证实了在MP染毒大鼠肝脏中观察到的肝细胞坏死、胆管增生、微泡空泡化和门脉炎等组织病理学改变，并为特定基因在所研究的毒理学过程中的作用提供了洞察力。
Methapyrilene (MP) exposure of animals can result in an array of adverse pathological responses including hepatotoxicity. This study investigates gene expression and histopathological alterations in response to MP treatment in order to 1) utilize computational approaches to classify samples derived from livers of MP treated rats based on severity of toxicity incurred in the corresponding tissue, 2) to phenotypically anchor gene expression patterns, and 3) to gain insight into mechanism( s) of methapyrilene hepatotoxicity. Large- scale differential gene expression levels associated with the exposure of male Sprague- Dawley rats to the rodent hepatic carcinogen MP for 1, 3, or 7 days after daily dosage with 10 or 100 mg/ kg/ day were monitored. Hierarchical clustering and principal component analysis were successful in classifying samples in agreement with microscopic observations and revealed low- dose effects that were not observed histopathologically. Data from cDNA microarray analysis corroborated observed histopathological alterations such as hepatocellular necrosis, bile duct hyperplasia, microvesicular vacuolization, and portal inflammation observed in the livers of MP exposed rats and provided insight into the role of specific genes in the studied toxicological processes.