Diesel exhaust influences carcinogenic PAH-induced genotoxicity and gene expression in human breast epithelial cells in culture.
The carcinogenic polycyclic aromatic hydrocarbon (PAHs) benzo[a]pyrene (B[a]P) and dibenzo[a,l]pyrene (DB[a,l]P) are widespread environmental pollutants, however their toxicological effects within a mixture is not established. We investigated the influence of diesel exhaust (DE) on B[a]P and DB[a,l]P-induced PAH-DNA adduct formation, metabolic activation, gene expression and 8-oxo-dG adduct levels in human breast epithelial cells (MCF-10A) in culture. Following 24 and 48h, cells co-exposed to DE plus B[a]P exhibited a significant decrease in PAH-DNA adduct levels, compared with B[a]P alone, as determined by (33)P-postlabeling combined with reversed-phase high performance liquid chromatography (HPLC). Cytochrome P450 (CYP) enzyme activity, as measured by the ethoxyresorufin O-deethylase (EROD) assay and CYP1B1 expression, significantly increased with co-exposure of DE plus DB[a,l]P, compared with DB[a,l]P alone. Aldo keto-reductase (AKR)1C1, AKR1C2, and AKR1C3 expression also significantly increased in cells exposed to DE plus PAH, compared with PAH exposure alone. Cell populations exhibiting 8-oxo-dG adducts significantly increased in response to exposure to B[a]P or DE plus B[a]P for 24h, compared with vehicle control, as quantified by flow cytometry. These results suggest that complex mixtures may modify the carcinogenic potency of PAH by shifting the metabolic activation pathway from the production of PAH diol-epoxides to AKR pathway-derived metabolites.
Courter
Lauren A
LA
Department of Environmental and Molecular Toxicology, 1007 Agriculture and Life Sciences Building, Oregon State University, Corvallis, OR 97331-7302, USA.
Pereira
Cliff
C
Baird
William M
WM
D000080242:8-Hydroxy-2'-Deoxyguanosine; D001483:Base Sequence; D001711:Biotransformation; D001942:Breast Feeding; D002274:Carcinogens, Environmental / Q000493:pharmacokinetics / Q000633:toxicity*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D011084:Polycyclic Aromatic Hydrocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D001335:Vehicle Emissions / Q000633:toxicity*
D002274:Carcinogens, Environmental; D018736:DNA Adducts; D017931:DNA Primers; D011084:Polycyclic Aromatic Hydrocarbons; D001335:Vehicle Emissions; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003577:Cytochrome P-450 Enzyme System; D003849:Deoxyguanosine