Ito Yuki, Yamanoshita Osamu, Asaeda Nobuyuki, Tagawa Yoshiaki, Lee Chul-Ho, Aoyama Toshifumi, Ichihara Gaku, Furuhashi Koichi, Kamijima Michihiro, Gonzalez Frank J, Nakajima Tamie
Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
J Occup Health. 2007 May;49(3):172-82. doi: 10.1539/joh.49.172.
Di(2-ethylhexyl)phthalate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPARalpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPARalpha, we compared DEHP-induced tumorigenesis in wild-type and Pparalpha-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 Pparalpha-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 PPARalpha. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Pparalpha-null than in wild-type mice. NFkappaB levels also significantly increased in a dose-dependent manner in Pparalpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Pparalpha-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 Pparalpha-null mice.
邻苯二甲酸二（2-乙基己基）酯（DEHP）是一种常用的工业增塑剂，可能通过激活过氧化物酶体增殖物激活受体α（PPARα）引发肝脏肿瘤。DEHP致瘤机制尚未完全阐明，为明确DEHP致瘤是否通过PPARα诱导，我们比较了野生型和Pparα基因敲除小鼠中DEHP诱导的肿瘤发生情况。每种基因型的小鼠分为三组，用含0、0.01%或0.05%DEHP的饲料处理22个月。令人惊讶的是，暴露于0.05%DEHP的Pparα基因敲除小鼠的肝脏肿瘤发生率（25.8%）高于同样暴露的野生型小鼠（10.0%）。这些结果表明存在独立于PPARα的DEHP诱导肝肿瘤发生的途径。两种基因型小鼠中8-OHdG水平均呈剂量依赖性增加，但Pparα基因敲除小鼠的增加程度高于野生型小鼠。在Pparα基因敲除小鼠中，NFκB水平也以剂量依赖性方式显著增加。原癌基因c-jun-mRNA被诱导，仅在喂食含0.05%DEHP饲料的Pparα基因敲除小鼠中c-fos-mRNA有诱导趋势。这些结果表明，DEHP暴露诱导的氧化应激增加可能导致炎症诱导和/或原癌基因表达，从而导致Pparα基因敲除小鼠肿瘤发生率较高。
