title: Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.
abstract: Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential toxic effects in the lung.
authors.affiliation: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505-2888, USA. jym1@cdc.gov
authors.forename: Jane Y C
authors.initials: JY
authors.lastname: Ma
authors.forename: Apavoo
authors.initials: A
authors.lastname: Rengasamy
authors.forename: Dave
authors.initials: D
authors.lastname: Frazer
authors.forename: Mark W
authors.initials: MW
authors.lastname: Barger
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hubbs
authors.forename: Lori
authors.initials: L
authors.lastname: Battelli
authors.forename: Seith
authors.initials: S
authors.lastname: Tomblyn
authors.forename: Samuel
authors.initials: S
authors.lastname: Stone
authors.forename: Vince
authors.initials: V
authors.lastname: Castranova
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000494:pharmacology; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis / Q000494:pharmacology; D004790:Enzyme Induction; D005260:Female; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000494:pharmacology; D006838:Hydrocarbons / Q000737:chemistry*; D007249:Inflammation; D019570:Inhalation Exposure; D007375:Interleukin-1 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000502:physiology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000494:pharmacology; D016273:Occupational Exposure; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism* / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015262:Xenobiotics / Q000378:metabolism
chemical_list: D006838:Hydrocarbons; D007375:Interleukin-1; D011084:Polycyclic Aromatic Hydrocarbons; D014409:Tumor Necrosis Factor-alpha; D015262:Xenobiotics; C006647:asphalt; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase