Rat pulmonary CYP1A1 induction is inhibited by respirable coal dust exposure.
Ghanem-M; Porter-D; Battelli-L; Kashon-M; Barger-M; Ma-JY; Vallyathan-V; Nath-J; Hubbs-A
Toxicologist 2003 Mar; 72(S-1):320-321
Cytochrome P450 1A1 (CYP1A1) metabolizes polycyclic aromatic hydrocarbons in cigarette smoke to reactive intermediates that can initiate lung cancer. We hypothesized that coal dust (CD) exposure might modify pulmonary carcinogenesis by altering pulmonary CYP1A1 induction. To test this hypothesis, we examined the ability of respirable CD particles (<5 microns) to inhibit pulmonary CYP1A1 induction. Male, Sprague Dawley rats (220-270g) were intratracheally exposed to 0, 2.5, 10, 20, 40 mg coal dust/rat or vehicle (saline). After 11 days, rats were injected intraperitoneally (IP) with the CYP1A1 inducer Beta-naphthoflavone (BNF: 50mg/kg IP). Three days later, rats were sacrificed and CYP1A1 activity in the lungs was measured as 7-ethoxyresorufin-O-deethylase (EROD) activity. CYP1A1 protein was determined by Western blot using polyclonal rabbit anti-rat CYP1A1 antibodies. Pulmonary inflammation was assessed by determining bronchoalveolar lavage polymorphonuclear (PMN) cell counts, alveolar macrophage (AM) chemiluminescence (CL), and nitric oxide (NO)-dependent AM chemiluminescence. EROD activity was suppressed by CD exposure in a dose-dependent fashion (R2= 0.932, p=0.008). Western blot showed a significant reduction of CYP1A1 protein in rats treated with 40 mg CD and BNF when compared with rats treated with BNF alone (p<0.05). CD exposed rats had a dose-dependent increase of PMN (R2=0.974, p= 0.002). AM count was significantly higher in all rats exposed to CD and BNF compared with rats treated with BNF alone. NO-dependent CL was also significantly increased in rats treated with 40 mg CD and BNF compared to rats treated with BNF alone (p= 0.004). These results suggest that coal dust exposure inhibits induction of CYP1A1 activity by BNF and enhances pulmonary inflammation, in a dose-dependent manner.
Pulmonary-system; Laboratory-animals; Animal-studies; Animals; Coal-dust; Dust-particles; Dusts; Particulate-dust; Particulates; Occupational-exposure; Exposure-levels; Polycyclic-aromatic-hydrocarbons; Pulmonary-system-disorders; Lung-cancer; Cigarette-smoking; Carcinogenesis
Work Environment and Workforce: Mixed Exposures
The Toxicologist. Society of Toxicology 42nd Annual Meeting and ToxExpo, Cutting-Edge Science, Networking, New Perspectives, March 9-13, 2003, Salt Lake City, Utah