Matsumoto Yutaka, Ide Fumio, Kishi Reiko, Akutagawa Tomoko, Sakai Shigekatsu, Nakamura Masafumi, Ishikawa Toshitaka, Fujii-Kuriyama Yoshiaki, Nakatsuru Yoko
Department of Public Health, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Environ Sci Technol. 2007 May 15;41(10):3775-80. doi: 10.1021/es062793g.
Urban particulate air pollution is associated with an increased incidence of cancers, and especially lung cancer. Organic extracts of airborne particulate matter (APM) cause cancer in mice, and PAHs adsorbed to APM are associated with particle-induced carcinogenesis. PAHs are agonists for AhR and are predominantly responsible for lung cancer through induction of highly carcinogenic metabolites. PAH metabolization requires CYP1A1 induction through activation of AhR, and therefore we hypothesized that carcinogenesis due to PAHs in APM would be reduced in AhR-/- mice. To examine this hypothesis, we performed a long-term continuous-application study of carcinogenesis in AhR-/- mice using airborne particulate extract (APE) of APM collected in Sapporo. Tumor development (squamous cell carcinoma) occurred in 8 of 17 AhR+/+ mice (47%), but no tumors were found in AhR-/-mice, and CYP1A1 was induced in AhR+/+ mice but not in AhR-/- mice. These results demonstrate that AhR plays a significant role in APE-induced carcinogenesis in AhR+/+ mice and CYP1A1 activation of carcinogenic PAHs is also of importance. Therefore, measurement of CYP1A1 induction in vitro may be useful for assessment of APM-induced carcinogenesis in humans. We also show that PAH-like compounds are major contributors to AhR-mediated carcinogenesis, whereas TCDD and related compounds make a smaller contribution.
城市空气中的颗粒物污染与癌症发病率增加有关，尤其是肺癌。空气中颗粒物（APM）的有机提取物可在小鼠体内诱发癌症，吸附在APM上的多环芳烃（PAHs）与颗粒物诱导的致癌作用有关。PAHs是芳烃受体（AhR）的激动剂，主要通过诱导高致癌性代谢物导致肺癌。PAH代谢需要通过激活AhR诱导细胞色素P450 1A1（CYP1A1），因此我们推测，APM中PAHs引起的致癌作用在AhR基因敲除小鼠中会减弱。为验证这一假设，我们使用在札幌收集的APM的空气颗粒物提取物（APE），对AhR基因敲除小鼠进行了长期连续应用致癌作用的研究。17只AhR+/+小鼠中有8只（47%）发生肿瘤（鳞状细胞癌），但AhR-/-小鼠未发现肿瘤，AhR+/+小鼠中诱导了CYP1A1，而AhR-/-小鼠中未诱导。这些结果表明，AhR在AhR+/+小鼠的APE诱导致癌作用中起重要作用，致癌性PAHs的CYP1A1激活也很重要。因此，体外测量CYP1A1诱导可能有助于评估人类APM诱导的致癌作用。我们还表明，类PAH化合物是AhR介导的致癌作用的主要贡献者，而2,3,7,8-四氯二苯并-对-二恶英（TCDD）及相关化合物的贡献较小。
