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Human exposure to the carcinogenic polycyclic aromatic hydrocarbons (PAHs) benzo[a]pyrene (B[a]P) and dibenzo[a,l]pyrene (DB[a,l]P) is through environmental complex mixtures, such as urban dust particulate matter (UDPM) and diesel exhaust (DE), however the potency of these PAH within a mixture is not established. To determine the effect of these mixtures on the carcinogenic potency of B[a]P and DB[a,l]P, tumor initiation, CYP-mediated metabolic activation, PAH-DNA adduct formation, oxidative DNA damage, and changes in gene expression were investigated. In SENCAR mice, both UDPM and DE decreased the tumor-initiating potency of B[a]P and DB[a,l]P, respectively. UDPM delayed the onset of B[a]P-induced tumor initiation, and DE decreased the overall tumor and carcinoma burden by DB[a,l]P. Short-term in vivo studies revealed decreased cytochrome P450 (CYP) induction and PAH-DNA adduct levels. These results were closely associated with results obtained in human breast epithelial cells in culture (MCF-10A), where UDPM and DE decreased the carcinogenic potency of B[a]P and DB[a,l]P by inhibition of CYP metabolic activity and PAH-DNA adduct levels. In vitro biochemical assays using pure CYP1A1 and CYP1B1 microsomal protein revealed that the aromatic component of UDPM and DE non-competitively inhibited CYP metabolic capacity. Quantitative real-time PCR experiments revealed that the expression of aldo-keto reductase (AKR) 1C1, 1C2, and 1C3 genes significantly increased upon co-exposure to either UDPM or DE plus PAH. Co-exposure to UDPM or DE plus PAH resulted in increased DNA strand breaks and 8-hydroxy-2’-deoxyguanosine (8-OH-dGuo) adducts, compared with PAH exposure alone. These data indicate that CYP inhibition by complex mixtures may result in the upregulation of the alternate, AKR-mediated PAH metabolism pathway thereby resulting in an increased production of reactive oxygen species (ROS). Taken together, the carcinogenic potency of PAH is dependent on the induction of bioactivation enzymes, and environmental complex mixtures have the ability to shift PAH metabolism pathways. |
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