Laboratory of Investigative Toxicology and Pathology, Department of Environmental Health, Indiana University School of Public Health, 1025 E 7th St, Bloomington, IN, 47405, USA.
Arch Toxicol. 2020 Aug;94(8):2873-2884. doi: 10.1007/s00204-020-02781-8. Epub 2020 May 20.
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.
狄氏剂已被证明可选择性地在小鼠中诱导肝肿瘤。尽管其确切机制尚未完全阐明，但我们实验室和其他实验室的先前研究表明，狄氏剂通过非遗传毒性机制在肿瘤促进阶段诱导小鼠肝肿瘤。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可能作用模式（MOA）的作用。在最初的研究中，雄性 C57BL/6 小鼠（6-8 周龄）用饮食中的狄氏剂（10ppm）处理 7、14 和 28 天。在这项研究中，将苯巴比妥（PB）、β-萘黄酮（BNF）和邻苯二甲酸二（2-乙基己基）酯（DEHP）作为阳性对照物，用于评估 CAR（组成型雄烷受体）、AhR（芳烃受体）或 PPARα（过氧化物酶体增殖物激活受体α）在狄氏剂肝癌发生的 MOA 中的参与。与未处理的对照组相比，处理组的肝细胞 DNA 合成（BrdU 掺入）显着增加。核受体反应基因表达的分析表明，狄氏剂诱导与 CAR 激活（Cyp2b10，高达 400-至 2700 倍）和 PXR 激活（Cyp3a11，高达 5-至 11 倍）特异性的基因表达显着增加。AhR 靶基因 Cyp1a1 和 Cyp1a2 也略有诱导（分别为 2.0-至 3.7 倍和 1.7-至 2.8 倍）。在用狄氏剂处理后，未观察到 PPARα 的激活。此外，与我们实验室的先前研究一致，用狄氏剂处理会显着增加肝脏的氧化应激。在使用 CAR、PXR 和 CAR/PXR 基因敲除小鼠的后续研究中，我们证实狄氏剂对小鼠的肝脏作用仅通过 CAR 受体的激活来介导。基于这些发现，我们提出狄氏剂通过核受体 CAR 介导的作用模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 激活后狄氏剂诱导肝肿瘤形成过程中的相关或修饰因素。
