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.

Genotoxic damage in female residents exposed to environmental air pollution in Shenyang city, China.

Air pollution has been suggested to cause genetic damage from investigations of many biological markers that measure cytogenetic damage in humans. Here, we evaluated the genotoxic effects of ambient air pollution by investigating the extent of cytogenetic damage in human blood lymphocytes from rural and industrial female residents of Shenyang city, China, using micronuclei assays and polymorphic analyses of metabolic enzyme and DNA repair genes. After adjustment for potential confounding factors including DNA polymorphisms, industrial female residents were found to have a higher micronuclei frequency. These results provide evidence that micronuclei assays are a sensitive indicator to air pollution-induced genotoxic effects in humans.

CYP1A1 inducing potential of airborne particulate extracts collected during a 25-year period (1975-2000).

Samples of airborne particles from Sapporo, the capital of Hokkaido, Japan, were collected between 1975 and 2000. Major polycyclic aromatic hydrocarbons (PAHs) included in the extracts of airborne particles were investigated for their mutagenicity and potential for inducing drug-metabolizing enzyme cytochrome P450 (CYP)1A1, which is considered to be responsible for the activation of PAHs in airborne particle extracts, as well as in cigarette smoke, to carcinogens and is associated with risk of several cancers. There was a dose-related increase in CYP1A1 activity in human lymphoblastoid cells after exposure to airborne particulates containing PAHs. The mutagenicity of the airborne particles collected in summer was lowest and for those collected in spring was lower than in autumn or winter. Likewise, the winter sample had the strongest CYP1A1 inducing potential while the summer sample had the weakest. CYP1A1 inducing potency was strongly related to the amount of benzo(k)fluorathene (Spearman's rank correlation coefficient (gamma) = 0.97), benzo[a]pyrene g = 0.96), benzo[g,h,i]perylene (gamma = 0.94), benz[a]anthracene (g = 0.93), chrysene (gamma = 0.93) in the extracts during the 25-year period, while the enzyme activity was measurably related to the amount of pyrene (gamma = 0.64) and fluorathene (gamma = 0.54). During the 25-year period, CYP1A1 inducing potential decreased every year together with a decrease in PAHs in the airborne particle extracts. CYP1A1 inducing potential may be one of the most convenient biomarkers with which to estimate the overall carcinogenicity/mutagenicity of airborne particle extracts.