Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor α-independent pathway
Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor α-independent pathway
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DOI：
10.1539/joh.49.172
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发表时间：
2007-05-01
影响因子：
3
通讯作者：
Nakajima, Tarnie
中科院分区：
文献类型：
--
作者：
Ito, Yuki;Yamanoshita, Osamu;Nakajima, Tarnie
二(2-乙基己基)邻苯二甲酸酯(DEHP)是一种常用的工业增塑剂，可能通过激活过氧化体增殖物激活受体α(PPAR(α))而导致肝肿瘤发生。DEHP的致瘤机制尚未完全阐明，为了阐明DEHP致瘤是否由PPARα诱导，我们在野生型和PPARα缺失的小鼠中比较了DEHP诱导的肿瘤形成。将每种基因型的小鼠分成3组，分别用含0、0.01和0.05%DEHP的饲料喂养22个月。令人惊讶的是，暴露于0.05%DEHP的Pparnull小鼠的肝脏肿瘤发生率(25.8%)高于类似暴露的野生型小鼠(10.0%)。这些结果表明，DEHP诱导的肝肿瘤发生存在独立于PPARa的途径。两种基因型小鼠的8-OHdG水平均呈剂量依赖性升高，但Pparnull小鼠的升高幅度高于野生型小鼠。在PPARα缺失小鼠中，核因子kappa B水平也以剂量依赖的方式显著增加。原癌基因c-jun-m RNA被诱导，而c-fos-m RNA倾向于仅在饲喂0.05%DEHP的PPARα缺失小鼠中被诱导。这些结果表明，DEHP暴露引起的氧化应激增加可能导致炎症和/或原癌基因的表达，从而导致PPARα缺失小鼠肿瘤的高发生率。
Di(2-ethyl hexyl) phthal ate (DEHP), a commonly used industrial plasticizer, causes liver tumorigenesis presumably via activation of peroxisome proliferator-activated receptor alpha (PPAR(alpha). The mechanism of DEHP tumorigenesis has not been fully elucidated, and to clarify whether DEHP tumorigenesis is induced via PPAR alpha, we compared DEHP-induced tumorigenesis in wild-type and Ppar alpha-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 Ppara-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 PPARa. The levels of 8-OHdG increased dose-dependently in mice of both genotypes, but the degree of increase was higher in Ppara-null than in wild-type mice. NF kappa B levels also significantly increased in a dose-dependent manner in Ppar alpha-null mice. The protooncogene c-jun-mRNA was induced, and c-fos-mRNA tended to be induced only in Ppar alpha-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 alpha-null mice.