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J Occup Health year 2008 volume 50 number 2 page 169 - 180
Classification Originals
Title Different Mechanisms of DEHP-induced Hepatocellular Adenoma Tumorigenesis in Wild-type and Ppara-null Mice
Author Kayoko Takashima1, 2, Yuki Ito3, Frank J Gonzalez4 and Tamie Nakajima3
Organization 1Department of Preventive Medicine, 2Institutes of Organ Transplants, Reconstructive Medicine and Tissue Engineering, Shinshu University Graduate School of Medicine, 3Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan and 4Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, USA
Keywords Di (2-ethylhexyl) phthalate, Peroxisome proliferator-activated receptor alpha, Tumorigenesis, Apoptotic peptidase activating factor 1, DNA-damage-inducible 45 alpha
Correspondence T. Nakajima, Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan (e-mail: tnasu23@med.nagoya-u.ac.jp)
Abstract Different Mechanisms of DEHP-induced Hepatocellular Adenoma Tumorigenesis in Wild-type and Ppara-null Mice: Kayoko Takashima, et al. Department of Preventive Medicine, Shinshu University Graduate School of Medicine-Di (2-ethylhexyl) phthalate (DEHP) exposure is thought to lead to hepatocellular hypertrophy and hyperplasia in rodents mediated via peroxisome proliferator-activated receptor alpha (PPARa). 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 Ppara-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 Ppara-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 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.