Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver
Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver
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DOI：
10.1016/j.tox.2004.06.014
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发表时间：
2004-10-15
期刊：
影响因子：
4.5
通讯作者：
Corton, JC
中科院分区：
文献类型：
--
作者：
Laughter, AR;Dunn, CS;Corton, JC
三氯乙烯 (TCE) 是一种工业溶剂，也是一种广泛的环境污染物。 TCE 诱导小鼠肝癌被认为是由两种致癌代谢物二氯乙酸 (DCA) 和三氯乙酸 (TCA) 介导的。 TCE 被认为是一种相对较弱的过氧化物酶体增殖剂 (PP)，是一组啮齿动物肝癌物质，通过 PP 激活受体 α (PPARα) 在肝脏中引起适应性反应。本研究的目的是确定 TCE 是否有影响。肝脏中与致癌相关的TCA和DCA是由PPAR介导的（x。雄性野生型和PPARα缺失小鼠通过灌胃给予TCE 3天或3周；TCA或DCA在饮用水中给予1周。TCE导致的相对肝脏和肾脏重量的增加依赖于PPARα，而DCA导致的肝脏重量增加与PPARα无关。 在 TCE 暴露后，在野生型小鼠中观察到肝细胞增殖的剂量依赖性增加（通过肝细胞的 BrdU 标记确定）是 PPARα 依赖性的。使用含有相似 1200 个基因的宏阵列进行的转录谱分析显示，在暴露于 TCE 后，野生型小鼠中观察到的所有表达变化中，93%（43 中的 40）依赖于 PPARα 并包括 PP（Cyp4a12，表皮生长因子受体）的已知靶标以及参与细胞生长的其他基因。接触 TCE、TCA 或 DCA 后，催化脂肪酸 β 和 omega 氧化的酶的增加取决于 PPARα。与对照组相比，TCE 改变了 PPARα 缺失小鼠肝脏中的一组独特基因。 野生型小鼠，包括那些对不同形式的压力做出反应的小鼠。这些数据支持这样的假设：PPARα 在介导 TCE 暴露后肝癌发生的相关影响中起主导作用。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
Trichloroethylene (TCE) is an industrial solvent and a widespread environmental contaminant. Induction of liver cancer in mice by TCE is thought to be mediated by two carcinogenic metabolites, dichloroacetate (DCA) and trichloroacetate (TCA). TCE is considered to be a relatively weak peroxisome proliferator (PP), a group of rodent hepatocarcinogens that cause adaptive responses in liver through the PP-activated receptor alpha (PPARalpha). The objectives of this study were to determine whether effects of TCE. TCA and DCA in the liver associated with carcinogenesis are mediated by PPAR(x. Male wild-type and PPARalpha-null mice were given TCE by gavage for 3 days or 3 weeks; TCA or DCA were given in the drinking water for 1 week. Increases in relative liver and kidney weights by TCE were dependent on PPARalpha whereas liver weight increases by DCA were PPARalpha-independent. Dose-dependent increases in hepatocyte proliferation observed in wild-type mice after TCE exposure as deter-mined by BrdU-Iabeling of heratocytes were PPARalpha-dependent. Transcript profiling using macroarrays containing similar to1200 genes showed that 93% (40 out of 43) of all expression changes observed in wild-type mice upon TCE exposure were dependent on PPARalpha and included known targets of PP (Cyp4a12, epidermal growth factor receptor) and additional genes involved in cell growth. Increases in enzymes that catalyze beta- and omega-oxidation of fatty acids were dependent on PPARalpha after exposure to TCE, TCA or DCA. TCE altered a unique set of genes in the livers of PPARalpha-null mice compared to wild-type mice including those that respond to different forms of stress. These data support the hypothesis that PPARalpha plays a dominant role in mediating the effects associated with hepatocarcinogenesis upon TCE exposure. (C) 2004 Elsevier Ireland Ltd. All rights reserved.