Dieldrin has been shown to induce liver tumors selectively in mice. Although the exact mechanism is not fully understood, previous studies from our laboratory and others have shown that dieldrin induced liver tumors in mice through a non-genotoxic mechanism acting on tumor promotion stage. Two studies were performed to examine the role of nuclear receptor activation as a possible mode of action (MOA) for dieldrin-induced mouse liver tumors. In the initial study, male C57BL/6 mice (6- to 8-week old) were treated with dieldrin in diet (10 ppm) for 7, 14, and 28 days. Phenobarbital (PB), beta-naphthoflavone (BNF) and Di (2-ethylhexyl) phthalate (DEHP) were included as positive controls in this study for evaluating the involvement of CAR (constitutive androstane receptor), AhR (aryl hydrocarbon receptor) or PPARα (peroxisome proliferator activated receptor alpha) in the MOA of dieldrin hepatocarcinogenesis. A significant increase in hepatocyte DNA synthesis (BrdU incorporation) was seen in treated mice compared with the untreated controls. Analysis of the expression of the nuclear receptor responsive genes revealed that dieldrin induced a significant increase in the expression of genes specific to CAR activation (Cyp2b10, up to 400- to 2700-fold) and PXR activation (Cyp3a11, up to 5- to 11-fold) over untreated controls. The AhR target genes Cyp1a1 and Cyp1a2 were also slightly induced (2.0- to 3.7-fold and 1.7- to 2.8-fold, respectively). PPARα activation was not seen in the liver following dieldrin treatment. In addition, consistent with previous studies in our lab, treatment with dieldrin produced significant elevation in the hepatic oxidative stress. In a subsequent study using CAR, PXR, and CAR/PXR knockout mice, we confirmed that the dieldrin-induced liver effects in mouse were only mediated by the activation of CAR receptor. Based on these findings, we propose that dieldrin induced liver tumors in mice through a nuclear receptor CAR-mediated mode of action. The previously observed oxidative stress/damage may be an associated or modifying factor in the process of dieldrin-induced liver tumor formation subsequent to the CAR activation.

中文翻译：

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本构雄激素受体（CAR）介导狄氏剂诱导的小鼠肝肿瘤发生。

狄氏剂已被证明可在小鼠中选择性诱导肝肿瘤。尽管尚未完全了解确切的机制，但我们实验室和其他实验室的先前研究表明，狄氏剂通过一种非肿瘤毒性机制作用于肿瘤的促进阶段，从而在小鼠体内诱发肝肿瘤。进行了两项研究，以检查核受体激活作为狄氏剂诱导的小鼠肝肿瘤的可能作用方式（MOA）的作用。在最初的研究中，雄性C57BL / 6小鼠（6至8周大）在饮食中（10 ppm）用狄氏剂处理了7天，14天和28天。苯巴比妥（PB），β-萘黄酮（BNF）和邻苯二甲酸二（2-乙基己基）酯（DEHP）被包括在本研究中作为阳性对照，用于评估CAR（组成型雄激素受体）的参与，狄氏剂肝癌发生的MOA中的AhR（芳烃受体）或PPARα（过氧化物酶体增殖物激活的受体α）。与未处理的对照相比，在处理的小鼠中观察到肝细胞DNA合成的显着增加（BrdU掺入）。对核受体反应性基因表达的分析表明，狄氏剂诱导了CAR激活（Cyp2b10，最多400至2700倍）和PXR激活（Cyp3a11，最多5至11）特异基因的表达显着增加。 -倍）。还轻微诱导了AhR靶基因Cyp1a1和Cyp1a2（分别为2.0至3.7倍和1.7至2.8倍）。狄氏剂治疗后在肝脏中未观察到PPARα活化。此外，与我们实验室先前的研究一致，用狄氏剂治疗可显着提高肝氧化应激。在随后的使用CAR，PXR和CAR / PXR基因敲除小鼠的研究中，我们证实了狄氏剂诱导的小鼠肝功能仅由CAR受体的激活介导。基于这些发现，我们建议狄氏剂通过核受体CAR介导的作用方式在小鼠中诱导肝肿瘤。先前观察到的氧化应激/损伤可能是CAR激活后狄尔德林诱导的肝肿瘤形成过程中的相关因素或修饰因素。我们提出狄氏剂通过核受体CAR介导的作用方式诱导小鼠肝肿瘤。先前观察到的氧化应激/损伤可能是CAR激活后狄尔德林诱导的肝肿瘤形成过程中的相关因素或修饰因素。我们提出，狄氏剂通过核受体CAR介导的作用方式诱导小鼠肝肿瘤。先前观察到的氧化应激/损伤可能是CAR激活后狄尔德林诱导的肝肿瘤形成过程中的相关因素或修饰因素。