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J Occup Health year 2007 volume 49 number 3 page 172 - 182
Classification Original
Title Di(2-ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator-activated Receptor -independent Pathway
Author Yuki ITO1, Osamu YAMANOSHITA2, Nobuyuki ASAEDA3, Yoshiaki TAGAWA3, Chul-Ho LEE1, Toshifumi AOYAMA4, Gaku ICHIHARA1, Koichi FURUHASHI1, Michihiro KAMIJIMA1,
Frank J. GONZALEZ5 and Tamie NAKAJIMA1
Organization 1Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine,
2Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, 3Safety Assessment Laboratory, Sanwa Kagaku Kenkyusho Co., Ltd., 4Department of Metabolic Regulation, Institute of Aging and Adaptation, Shinshu University Graduate School of Medicine, Japan and 5Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, USA
Keywords Di(2-ethylhexyl)phthalate, Ppar-null mouse, Tumorigenesis, NFB, 8-OHdG, c-jun, Inflammation
Correspondence T. Nakajima, Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan (e-mail: tnasu23@med.nagoya-u.ac.jp)
Abstract Di(2-ethylhexyl)phthalate Induces Hepatic Tumorigenesis through a Peroxisome Proliferator-activated Receptor _-independent Pathway: Yuki ITO, et al. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine-Di(2-ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPAR). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPAR, we compared DEHP-induced tumorigenesis in wild-type and Ppar-null mice. Mice of each genotype were divided into three groups, and treated for 22 months with diets containing 0, 0.01 or 0.05% DEHP. Surprisingly, the incidence of liver tumors was higher in Ppar-null mice exposed to 0.05% DEHP (25.8%) than in similarly exposed wild-type mice (10.0%). These results suggest the existence of pathways for DEHP-induced hepatic tumorigenesis that are independent of PPAR. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Ppar-null than in wild-type mice. NFB levels also significantly increased in a dose-dependent manner in Ppar-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Ppar-null mice fed a 0.05% DEHP-containing diet. These results suggest that increases in oxidative stress induced by DEHP exposure may lead to the induction of inflammation and/or the expression of protooncogenes, resulting in a high incidence of tumorigenesis in Ppar-null mice.