Title: The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo.

Authors: Courter, Lauren A; Luch, Andreas; Musafia-Jeknic, Tamara; Arlt, Volker M; Fischer, Kay; Bildfell, Robert; Pereira, Cliff; Phillips, David H; Poirier, Miriam C; Baird, William M

Published In Cancer Lett, (2008 Jun 28)

Abstract: The carcinogenic effects of individual polycyclic aromatic hydrocarbons (PAH) are well established. However, their potency within an environmental complex mixture is uncertain. We evaluated the influence of diesel exhaust particulate matter on PAH-induced cytochrome P450 (CYP) activity, PAH-DNA adduct formation, expression of certain candidate genes and the frequency of tumor initiation in the two-stage Sencar mouse model. To this end, we monitored the effects of treatment of mice with diesel exhaust, benzo[a]pyrene (BP), dibenzo[a,l]pyrene (DBP), or a combination of diesel exhaust with either carcinogenic PAH. The applied diesel particulate matter (SRM(1975)) altered the tumor initiating potency of DBP: a statistically significant decrease in overall tumor and carcinoma burden was observed following 25 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA), compared with DBP exposure alone. From those mice that were treated at the beginning of the observation period with 2 nmol DBP all survivors developed tumors (9 out of 9 animals, 100%). Among all tumors counted at the end, nine carcinomas were detected and an overall tumor incidence of 2.6 tumors per tumor-bearing animal (TBA) was determined. By contrast, co-treatment of DBP with 50mg SRM(1975) led to a tumor rate of only 66% (19 out of 29 animals), occurrence of only three carcinomas in 29 animals and an overall rate of 2.1 tumors per TBA (P=0.04). In contrast to the results with DBP, the tumor incidence induced by 200 nmol BP was found slightly increased when co-treatment with SRM(1975) occurred (71% vs. 85% after 25 weeks). Despite this difference in tumor incidence, the numbers of carcinomas and tumors per TBA did not differ statistically significant between both treatment groups possibly due to the small size of the BP treatment group. Since bioactivation of DBP, but not BP, predominantly depends on CYP1B1 enzyme activity, SRM(1975) affected PAH-induced carcinogenesis in an antagonistic manner when CYP1B1-mediated bioactivation was required. The explanation most likely lies in the much stronger inhibitory effects of certain PAHs present in diesel exhaust on CYP1B1 compared to CYP1A1. In the present study we also found molecular markers such as highly elevated AKR1C21 and TNFRSF21 gene expression levels in tumor tissue derived from animals co-treated with SRM(1975) plus DBP. Therefore we validate microarray data as a source to uncover transcriptional signatures that may provide insights into molecular pathways affected following exposure to environmental complex mixtures such as diesel exhaust particulates.

PubMed ID: 18353537

MeSH Terms: Animals; Aryl Hydrocarbon Hydroxylases/metabolism; Benzo(a)pyrene/toxicity; Benzopyrenes/toxicity; Carcinogens/toxicity*; Cell Transformation, Neoplastic/chemically induced; Cell Transformation, Neoplastic/metabolism; Cytochrome P-450 CYP1A1/metabolism; Cytochrome P-450 CYP1B1; DNA Adducts/metabolism; DNA Damage*; Mice; Mice, Inbred SENCAR; Particulate Matter/toxicity*; Polycyclic Aromatic Hydrocarbons/metabolism; Polycyclic Aromatic Hydrocarbons/toxicity*; Skin Neoplasms/chemically induced*; Skin Neoplasms/metabolism; Tetradecanoylphorbol Acetate/pharmacology; Vehicle Emissions/toxicity*