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

芳烃受体（AhR或二恶英受体）是一种配体激活的转录因子，被认为介导多效性生物反应，例如致畸、肿瘤诱导、上皮增生和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还结合存在于环境污染物（如香烟烟雾和柴油机废气）中的致癌芳烃（AH）。我们用AhR基因敲除小鼠致癌实验研究了AhR对苯并[a]芘（BP）诱发的皮肤肿瘤的作用。为了研究AhR对其他致癌AH的致癌作用，我们研究了AhR基因敲除小鼠经二苯并[a，l]芘（DB[a，l]P）处理后的增殖反应和肿瘤诱导。DB[a，l]P处理6天后AhR+/+小鼠皮肤的BrdU标记指数显著高于AhR-/-小鼠。在AhR+/+和AhR-/-小鼠中也检测到遗传毒性应激反应引起的p53和p21积累，并且与AhR-/-小鼠相比，AhR+/+小鼠中p53或p21阳性细胞的发生率显著更高。AhR（-/-）和（+/+）小鼠的基因型每周用6 μg DB[a，l]P在背部上涂抹，持续24周。实验开始后24周，荷瘤小鼠的百分比分别为AhR（-/-）、100%和（+/+）30%。AhR+/+小鼠皮肤中出现恶性鳞状细胞癌（24%），但AhR-/-小鼠中未检测到恶性肿瘤。

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.