Role of carcinogenesis in aromatic hydrocarbons in Ah (dioxin) receptor knockout mice

Ah（二恶英）受体敲除小鼠中芳香烃致癌的作用

• 批准号: 11670205
• 负责人: NAKATSURU Yoko
• 金额: $ 2.3万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670205/
• 关键词: AhR gene; Knockout mice; Benzo[a]pyrene; DMBA; Dibenzo[a, l]pyrene; CYP1A1; CYP1B1; Progression; 発がん感受性; 芳香族炭化水素; p450CYP1A1; 薬物代謝酵素; 転写誘導

The aryl hydrocarbon receptor (AhR or dioxin receptor) is a ligand-activated transcription factor that is considered to mediate pleiotropic biological responses such as teratogenesis, tumor induction, epithelial hyperplasia and the induction of drug-metabolizing enzymes to environmental contaminants usually represented by dioxin. AhR also bind carcinogenic aromatic hydrocarbons (AH) which is present in environmental contaminants, such as cigarette smoke and diesel exhaust. We have reported that AhR is improtant to benzo[a]pyrene (BP) induced skin tumors using AhR gene knockout mouse carcinogenesis test. In this report, to investigate the carcinogenic role of AhR on other carcinogenic AH, we examined proliferative responses and tumor induction in AhR gene knockout mice after treatment with dibenzo[a, l]pyrene (DB[a, l]P). BrdU labeling indices of the skins from AhR+/+ mice 6 days after treatment with DB[a, l]P were significantly higher than in AhR-/- mice. Accumulation of p53 and p21 by the response of genotoxic stress was also immunohistochemically detected in both AhR+/+ and AhR-/- mice, and the incidence of p53 or p21 positive cells were significantly higher in AhR+/+ mice compared to AhR-/- mice. The genotypes of AhR (-/-) and (+/+) mice were painted with 6 μg of DB[a, l]P on the back weekly for 24 weeks. Percentage of tumor bearing mice 24 weeks after the start of experiments were AhR (-/-) ; 100%, and (+/+) 30%, respectively. Malignant squamous cell carcinomas developed in AhR+/+ mouse skin (24%), but no malignant tumor was detected in AhR-/- mice.

芳烃受体（AhR 或二恶英受体）是一种配体激活的转录因子，被认为可介导多效性生物反应，例如致畸、肿瘤诱导、上皮增生以及对通常以二恶英为代表的环境污染物的药物代谢酶的诱导。 AhR 还与环境污染物（例如香烟烟雾和柴油机尾气）中存在的致癌芳香烃 (AH) 结合。使用 AhR 基因敲除小鼠致癌试验，AhR 对苯并[a]芘 (BP) 诱导的皮肤肿瘤至关重要。在本报告中，为了研究 AhR 对其他致癌性 AH 的致癌作用，我们检查了 AhR 基因敲除中的增殖反应和肿瘤诱导。用二苯并[a,l]芘治疗后的小鼠（AhR+/+小鼠皮肤的DB[a,l]P标记指数）。 DB[a, l]P 显着高于 AhR-/- 小鼠。在 AhR+/+ 和 AhR-/- 小鼠中也通过免疫组织化学检测到 p53 和 p21 的积累，以及 p53 的发生率。与 AhR-/- 小鼠相比，AhR+/+ 小鼠或 p21 阳性细胞显着较高。AhR (-/-) 和 (+/+) 小鼠的基因型涂有 6。实验开始 24 周后，每周将 DB[a, l]P 置于背部，AhR 百分比分别为 (-/-) 和 (+/+) 30%。 AhR+/+ 小鼠皮肤中出现恶性鳞状细胞癌（24%），但在 AhR-/- 小鼠中未检测到恶性肿瘤。

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