Coal dust is a modifier of pulmonary CYP1A1 induction in rats.
Ghanem-M; Battelli-L; Kashon-M; Vallyathan-V; Ma-JY; Barger-M; Nath-J; Castranova-V; Hubbs-AF
Toxicologist 2002 Mar; 66(1-S):19
Cytochrome P4501Al (CYP1A1) plays an important role in pulmonary carcinogenesis. Pulmonary CYP1Al metabolizes inhaled exogenous agents such as cigarette smoke-associated polycyclic aromatic hydrocarbons, into potent carcinogens. We hypothesized that intrapulmonary deposition of particulate might modify susceptibility to inhaled carcinogens by modifying induction and activity of pulmonary CYP1A1. To test this hypothesis male Sprague-Dawley rats were intratracheally instilled with 0, 2.5., or 10 mg of respirable coal dust or iron oxide. Saline was instilled as a control. Eleven days later they were treated with the CYP1A1 inducer (beta-naphthoflavone (NF; 50 mg/kg IP) or vehicle (corn oil). Three days after that. they were sacrificed and the level of functional CYP1A1 in the lungs was measured as ethoxyresorufin-O-deethylase (EROD) activity. Lung CYP1A1 protein induction and localization of CVP1A1 protein to alveolar type II cells was assessed by dual immunofluorescence staining for CYP1A1 and cytokeratin 8 (a cytoskeletal protein expressed in type II cells). We found that pulmonary EROD activity was significantly greater in coal dust/NF and iron oxide/NF rats than in saline/NF rats. Increasing coal dust lung burden accentuated the enhancement of ERGO induction while increasing iron oxide lung burden diminished the enhancement seen at the lower lung burden. Immunofluorescence demonstrated that within the alveolus. a smaller proportion of CYP1A1 staining was associated with alveo1ar type II cells in coal dust/NF or iron oxide/NF rats than in saline/NF rats. These findings demonstrate that pulmonary exposure to coal dust modifies the inducibility and localization of CYP1A1 in the lung. These results suggest that respirable coal dust is not a simple co-variable in mixed exposures but a complex modifier of CYPlAl induction that alters CYP1A1 activity and localization in the lung.
Coal-dust; Pulmonary-cancer; Particulate-dust; Animal-studies; Iron-oxides; Lung-burden; Laboratory-animals; Respiratory-system-disorders; Pulmonary-system-disorders
Work Environment and Workforce: Mixed Exposures
The Toxicologist. Society of Toxicology 41st Annual Meeting and ToxExpo, March 17-21, 2002, Nashville, Tennessee