Aryl hydrocarbon receptor plays a significant role in mediating airborne particulate-induced carcinogenesis in mice.
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.
Matsumoto
Yutaka
Y
Department of Public Health, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. ytmatsu@zpost.plala.or.jp
Ide
Fumio
F
Kishi
Reiko
R
Akutagawa
Tomoko
T
Sakai
Shigekatsu
S
Nakamura
Masafumi
M
Ishikawa
Toshitaka
T
Fujii-Kuriyama
Yoshiaki
Y
Nakatsuru
Yoko
Y
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D004147:Dioxins / Q000032:analysis; D004790:Enzyme Induction / Q000187:drug effects; D005838:Genotype; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D009369:Neoplasms / Q000473:pathology*; D052638:Particulate Matter / Q000737:chemistry / Q000633:toxicity*; D011084:Polycyclic Aromatic Hydrocarbons / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism*; D012867:Skin / Q000187:drug effects / Q000201:enzymology
D004147:Dioxins; D052638:Particulate Matter; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; C020887:dibenzo(1,4)dioxin