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Biomarker Alterations Produced in Rat Lung by Intratracheal Instillations of Air Particulate Extracts and Chemoprevention with Oral N-acetylcysteine¹

Institute of Hygiene and Preventive Medicine, University of Genoa, Via A. Pastore I. I-16132 Genoa [A. I., A. C., F. D., S. D. F.]; Institute of Hygiene and Preventive Medicine, University of Catania, Via Biblioteca 4, I-95124 Cantania [S. S., F. D. N. P.]; and Institute of General Physiology, University of Genoa, Corso Europa 26, I-16132 Genoa [C. F. C.], Italy

Organic matter extracts were obtained from particulates recovered from 10,000-m³ air samples collected in Sicily (Italy). The overall concentrations of acenaphthene, benzo(a)pyrene, phenanthrene, anthracene, fluoranthene, and pyrene were 526 ng/m³ air in a highly polluted urban area and 48 ng/m³ in a rural area affected by motor vehicle traffic pollution. After metabolic activation, both samples were mutagenic in Salmonella typhimurium his strains of the TA and YG series, with potencies in TA100 of 140.7 and 11.8 revertants/m³ air, respectively. The samples, resuspended in tricaprylin, were instilled intratracheally in Sprague-Dawley rats for 5 consecutive days, accounting for a cumulative dose in each animal of the organic fractions extracted from 400 m³ air, which corresponds approximately to the volume of air inhaled by a man in 1 month. Treatment with the rural area sample and, at higher levels, with the urban area sample resulted in the formation of adducts to lung DNA, as assessed both by synchronous fluorescence spectrophotometry and by ³²P postlabeling, which showed the appearance of up to six individual adducts emerging from diffuse diagonal radioactive zones. The adducts were more efficiently detected by extraction with butanol than by digestion with nuclease P1. DNA binding of air particulate extracts was followed by alterations of early damage biomarkers only in the rats treated with the urban area sample. Repair of DNA damage in lung cells was inferred from a significant stimulation of the nuclear enzyme poly(ADP-ribose) polymerase compared with that in sham-exposed rats. Among the cells recovered by bronchoalveolar lavage, an increase in polymorphonucleate leulocytes and cells of the ciliated respiratory epithelium was accompanied by a relative decrease in pulmonary alveolar macrophages. The frequency of micronuclei was significantly enhanced both in epithelial cells and alveolar macrophages, and binucleated macrophages were also more frequent in treated rats. The thiol N-acetylcysteine, one of the most promising cancer chemopreventive agents, was administered with drinking water to a group of animals receiving the air particulate polycyclic aromatic hydrocarbon fraction from the urban area. N-acetylcysteine prevented or considerably attenuated the alterations of all monitored parameters. These findings provide evidence that, even under outstandingly high exposure conditions, it is possible to protect the respiratory tract from DNA-binding and DNA-damaging air particulate carcinogens.

¹ This study was supported by the National Research Council [Consiglio Nazionale delle Richerche-Ente Nationale Energia Electtrica (ENEL) Project on Interaction of Energetic Systems with Human and Environmental Health and Consiglio Nazionale delle Richerche Targeted Project Prevention and Control of Disease Factors (FATMA)].

² To whom requests for reprints should be addressed. Phone: (39) 10-353-8500; Fax: (39) 10-353-8504.

Received 10/18/95. Accepted 1/31/96.

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