Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Pparα-null mice
Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and Pparα-null mice
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DOI：
10.1539/joh.l7105
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发表时间：
2008-03-01
影响因子：
3
通讯作者：
Nakajima, Tamie
中科院分区：
文献类型：
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作者：
Takashima, Kayoko;Ito, Yuki;Nakajima, Tamie
邻苯二甲酸二（2-乙基己基）酯（DEHP）暴露被认为可通过过氧化物酶体增殖物激活受体α（PPAR（x）介导导致啮齿动物肝细胞肥大和增生。最近的一项研究表明，长期暴露于相对低剂量的DEHP（0.05%）导致肝肿瘤，包括肝细胞癌、肝细胞腺瘤和胆管细胞癌，在Ppar α缺失小鼠（25.8%）中的发生率高于野生型小鼠（10.0%）。使用具有肝细胞腺瘤的组织，进行微阵列（Affyssin MOE 430 A）以及部分实时定量PCR分析，以阐明两种基因分型小鼠中DEHP暴露导致的腺瘤形成机制。芯片图谱显示，暴露于DEHP的野生型和Ppar α缺失小鼠肝细胞腺瘤组织中上调或下调的基因有很大差异。在暴露于DEHP的野生型小鼠肝细胞腺瘤组织中，凋亡肽酶激活因子1（Apaf 1）和DNA损伤诱导45 α（Gadd 45 a）的基因表达增加，而在Ppara基因敲除小鼠的相应组织中它们没有变化。另一方面，细胞周期蛋白B2和髓细胞白血病序列1的表达仅在Ppara基因敲除小鼠的肝细胞腺瘤组织中增加。综上所述，DEHP可能部分通过抑制Gadd 45 a调控的G2/M期阻滞和Ppara缺失小鼠的caspase 3依赖性细胞凋亡诱导肝细胞腺瘤，但这些基因可能不参与野生型小鼠的肿瘤发生。与此相反，Met的表达水平显着增加，在野生型小鼠的肝腺瘤组织中，这可能表明Met参与DEHP诱导的野生型小鼠的肿瘤发生。
Di (2-ethylhexyl) phthalate (DEHP) exposure is thought to lead to hepatocellular hypertrophy and hyperplasia in rodents mediated via peroxisome proliferator-activated receptor alpha (PPAR(x). A recent study revealed that long-term exposure to relatively low-dose DEHP (0.05%) caused liver tumors including hepatocellular carcinomas, hepatocellular adenomas, and chologiocellular carcinomas at a higher incidence in Ppar alpha-null mice (25.8%) than in wild-type mice (10.0%). Using tissues with hepatocellular adenoma, microarray (Affymetrix MOE430A) as well as, in part, real-time quantitative PCR analysis was conducted to elucidate the mechanisms of the adenoma formation resulting from DEHP exposure in both genotyped mice. The microarray profiles showed that the up- or down-regulated genes were quite different between hepatocellular adenoma tissues of wild-type and Ppar alpha-null mice exposed to DEHR The gene expressions of apoptotic peptidase activating factor 1 (Apaf1) and DNA-damage-inducible 45 alpha (Gadd45a) were increased in the hepatocellular adenoma tissues of wild-type mice exposed to DEHP, whereas they were unchanged in corresponding tissues of Ppara-null mice. On the other hand, the expressions of cyclin B2 and myeloid cell leukemia sequence 1 were increased only in the hepatocellular adenoma tissues of Ppara-null mice. Taken together, DEHP may induce hepatocellular adenomas, in part, via suppression of G2/M arrest regulated by Gadd45a and caspase 3-dependent apoptosis in Ppara-null mice, but these genes may not be involved in tumorigenesis in the wild-type mice. In contrast, the expression level of Met was notably increased in the liver adenoma tissue of wild-type mice, which may suggest the involvement of Met in DEHP-induced tumorigenesis in wild-type mice.