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FORMATION OF 8-OXO-7, 8-DIHYDRO-2'-DEOXYGUANOSINE IN RAT LUNG FOLLOWING SUB-CHRONIC INHALATION OF CARBON BLACK
Citation:
Gallagher, J, R. L. Sams, J Inmon, R. Gelein, A. Elder, G. Oberdorster, AND A. Prahalad. FORMATION OF 8-OXO-7, 8-DIHYDRO-2'-DEOXYGUANOSINE IN RAT LUNG FOLLOWING SUB-CHRONIC INHALATION OF CARBON BLACK. Academic Press (ed.), JOURNAL OF TOXICOLOGY AND PHARMACOLOGY. Elsevier Science BV, Amsterdam, Netherlands, 190:224-231.
Description:
ABSTRACT
Formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine, an oxidative adduct in the lung DNA of rats following sub-chronic inhalation of carbon black. Gallagher, J., Sams II, R.L., Inmon, J., Gelein, R., Elder, A., Oberdorster, G., Prahalad, A. (2002). Toxicol. Appl. Pharmacol. XXX, xxx-xxx.
Chronic inhalation of carbon black (CB) can produce carcinomas in rat lungs. The mechanisms underlying this response are uncertain. It has been hypothesized that chronic inflammation and cell proliferation may play a role in the development of tumors after high dose, long-term contact of the particles with lung epithelial cells. In this investigation, we analyzed the formation of a known mutagenic lesion (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) in the lung DNA of rats following sub-chronic inhalation of CB (Printex-90 and Sterling V). Briefly, female Fischer 344 rats were exposed for 6 hr/day, 5 days/week for 13 weeks to 1, 7, and 50 mg/m3 of Printex-90 and at 50 mg/m3 of Sterling V CB. The formation of 8-oxo-dG in the lung DNA was assessed using a reverse phase HPLC system coupled with ultraviolet (UV) and electrochemical (EC) detection. After 13 weeks of exposure, measurements were made on lung samples obtained at the end of the exposure and a 44-week recovery period in clean air. Lung burdens of CB were determined at both time points as well as differential cell populations from bronchoalveolar lavage fluid (BAL). The results indicate that lung particle overload was achieved after exposure to 7 and 50 mg/m3 (Printex-90 and Sterling V) but not at 1 mg/m3 (Printex-90). Consistent with these results, a significant increase (p<0.05) in 8-oxo-dG induction was observed following 13 weeks of exposure to 50 mg/m3 Printex-90 and at 7 and 50 mg/m3 after the 44-week recovery period. No increase in 8-oxo-dG was observed for Sterling V CB at either time point. Additionally an increase (p<0.05) in neutrophils was observed at 7 mg/m3 (Printex-90) and 50 mg/m3 (Printex-90 and Sterling V, 13-week exposure period) and again at 50 mg/m3 (Printex-90 and Sterling V, 44-week recovery period). A significant elevation (p<0.05) of 8-oxo-dG when compared to control animals for the 7 mg/m3 exposure group with Printex-90 was detected at the 44-week recovery period but not with the 13 week exposure group, suggesting that high dose inhalation and lung deposition of CB causes continued perturbation within pulmonary tissue. Additionally the formation of 8-oxo-dG appeared to be dependent upon the physical characteristics of the CB material (Printex-90 vs. Sterling V). Our current findings suggest that prolonged, high dose exposure to CB can promote oxidative DNA damage which is consistent with the hypothesis that inflammatory cell-derived oxidants may play a role in the pathogenesis of rat lung tumors following long-term high dose exposure to CB in rats.