Different Mechanisms of DEHP-induced Hepatocellular Adenoma Tumorigenesis in Wild-type and Pparα-null Mice
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概要
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Di (2-ethylhexyl) phthalate (DEHP) exposure is thought to lead to hepatocellular hypertrophy and hyperplasia in rodents mediated via peroxisome proliferator-activated receptor alpha (PPARα). 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 Pparα-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 Pparα-null mice exposed to DEHP. 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 Pparα-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 Pparα-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.
著者
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NAKAJIMA TAMIE
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine
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ITO Yuki
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine
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GONZALEZ Frank
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
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Nakajima Tamie
Department Of Occupational And Environmental Health Nagoya University Graduate School Of Medicine
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TAKASHIMA Kayoko
Department of Preventive Medicine, Shinshu University Graduate School of Medicine
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Gonzalez Frank
Laboratory Of Metabolism National Cancer Institute National Institutes Of Health
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Ito Yuki
Department Of Biotechnology National Institute Of Agrobiological Resources Ministry Of Agriculture F
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Gonzalez Frank
Laboratory Of Metabolism Division Of Basic Science National Cancer Institute
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Nakajima Tamie
Department Of Hygiene School Of Medicine Shinshu University
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Takashima Kayoko
Department Of Preventive Medicine Shinshu University Graduate School Of Medicine:institutes Of Organ
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