Characterization of Peroxisome Proliferator-Activated Receptor α-Independent Effects of PPARα Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate also Activates the Constitutive-Activated Receptor
Characterization of Peroxisome Proliferator-Activated Receptor α-Independent Effects of PPARα Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate also Activates the Constitutive-Activated Receptor
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DOI：
10.1093/toxsci/kfp251
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发表时间：
2010-01-01
影响因子：
3.8
通讯作者：
Corton, J. Christopher
中科院分区：
文献类型：
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作者：
Ren, Hongzu;Aleksunes, Lauren M.;Corton, J. Christopher
过氧化物酶体增殖物化学物质(PPC)被认为通过核受体PPARα介导其对啮齿动物肝细胞生长和肝癌的影响。最近的研究表明，增塑剂邻苯二甲酸二(2-乙基己基)酯(DEHP)增加了PPARα缺失小鼠的肝脏肿瘤的发生率。我们假设一些PPC，包括DEHP，诱导转录变化不依赖于PPARα，但依赖于其他核受体，包括介导苯巴比妥(PB)对肝细胞生长和肝肿瘤诱导作用的结构性激活受体(CAR)。为了确定CAR在PPC的调节作用中的潜在作用，对已发表的大鼠和小鼠暴露于PPC的研究中的转录谱进行了荟萃分析，并将其与PB暴露产生的转录谱进行了比较。丙戊酸、氯贝特和DEHP在大鼠肝脏中和DEHP在小鼠肝脏中诱导的基因，包括已知受CAR调控的Cyp2b家族成员。用Affymetrix ST 1.0阵列和逆转录-聚合酶链式反应检测DEHP处理的野生型、PPARα缺失和CAR缺失小鼠肝脏中的转录变化表明：(1)DEHP诱导的大部分(类似于94%)PPARα依赖的转录变化；(2)许多PPARα不依赖于PB的基因；(3)DEHP诱导的Cyp2b10、Cyp3a11和Metals thionine-1基因依赖于CAR，但PPAR不依赖于Car；(4)一些基因(Cyp8b1、Gmst4和Gstm7)的诱导不依赖CAR和PPARα。我们的结果表明，暴露于包括DEHP在内的PPARα激活剂会导致啮齿动物肝脏中多种核受体的激活。
Peroxisome proliferator chemicals (PPC) are thought to mediate their effects in rodents on hepatocyte growth and liver cancer through the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha. Recent studies indicate that the plasticizer di-(2-ethylhexyl) phthalate (DEHP) increased the incidence of liver tumors in PPAR alpha-null mice. We hypothesized that some PPC, including DEHP, induce transcriptional changes independent of PPAR alpha but dependent on other nuclear receptors, including the constitutive-activated receptor (CAR) that mediates phenobarbital (PB) effects on hepatocyte growth and liver tumor induction. To determine the potential role of CAR in mediating effects of PPC, a meta-analysis was performed on transcript profiles from published studies in which rats and mice were exposed to PPC and compared the profiles to those produced by exposure to PB. Valproic acid, clofibrate, and DEHP in rat liver and DEHP in mouse liver induced genes, including Cyp2b family members that are known to be regulated by CAR. Examination of transcript changes by Affymetrix ST 1.0 arrays and reverse transcription-PCR in the livers of DEHP-treated wild-type, PPAR alpha-null, and CAR-null mice demonstrated that (1) most (similar to 94%) of the transcriptional changes induced by DEHP were PPAR alpha-dependent, (2) many PPAR alpha-independent genes overlapped with those regulated by PB, (3) induction of genes Cyp2b10, Cyp3a11, and metallothionine-1 by DEHP was CAR dependent but PPAR alpha-independent, and (4) induction of a number of genes (Cyp8b1, Gstm4, and Gstm7) was independent of both CAR and PPAR alpha. Our results indicate that exposure to PPAR alpha activators including DEHP leads to activation of multiple nuclear receptors in the rodent liver.