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ToxSci Advance Access published online on October 23, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl137
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 4, 2006
Accepted October 16, 2006

Carcinogenicity

Urban Dust Particulate Matter Alters PAH-Induced Carcinogenesis by Inhibition of CYP1A1 and CYP1B1

Lauren A. Courter 1, Tamara Musafia-Jeknic 1, Kay Fischer 2, Robert Bildfell 2, Jack Giovanini 3, Cliff Pereira 3, and William M. Baird 1 *

1 Department of Environmental and Molecular Toxicology, 1007 Agriculture and Life Sciences Bldg., Oregon State University, Corvallis, Oregon 97331, USA
2 College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
3 Department of Statistics, Oregon State University, Corvallis, Oregon 97331, USA

* To whom correspondence should be addressed.
William M. Baird, E-mail: william.baird{at}oregonstate.edu


  Abstract

The polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and dibenzo[a,l]pyrene (DB[a,l]P) are well-studied environmental carcinogens, however their potency within a complex mixture is uncertain. We investigated the influence of urban dust particulate matter (UDPM) on the bioactivation and tumor initiation of B[a]P and DB[a,l]P in an initiation-promotion tumorigenesis model. SENCAR mice were treated topically with UDPM or in combination with B[a]P or DB[a,l]P, followed by weekly application of the promoter 12-O-tetradecanoylphorbol-13 acetate. UDPM exhibited weak tumor-initiating activity, but significantly delayed the onset of B[a]P-induced tumor initiation by two-fold. When co-treated with UDPM, DB[a,l]P treated animals displayed no significant difference in tumor initiating activity, compared with DB[a,l]P alone. Tumor initiation correlated with PAH-DNA adducts, as detected by 33P-postlabeling and reversed-phase HPLC. Induction of cytochrome P450 (CYP)1A1 and 1B1 proteins were also detected following UDPM treatment or co-treatment with B[a]P or DB[a,l]P, indicating PAH bioactivation. Further genotoxicity analyses by the comet assay revealed that co-treatment of UDPM plus B[a]P or DB[a,l]P resulted in increased DNA strand breaks, compared with PAH treatment alone. The metabolizing activities of CYP1A1 and CYP1B1, as measured by the 7-ethoxyresorufin O-deethylation (EROD) assay, revealed that UDPM non-competitively inhibited CYP1A1 and CYP1B1 EROD activity in a dose-dependent manner. Overall, these data suggest that components within complex mixtures can alter PAH-induced carcinogenesis by inhibiting CYP bioactivation and influence other genotoxic effects, such as oxidative DNA damage. These data further suggest that in addition to the levels of potent PAH, the effects of other mixture components must be considered when predicting human cancer risk.

Keywords: polycyclic aromatic hydrocarbons; benzo[a]pyrene; dibenzo[a,l]pyrene; cytochrome P450; aldo-keto reductase; air pollution.
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