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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 492-498

Quartz Exposure of the Rat Lung Leads to a Linear Dose Response in Inflammation but Not in Oxidative DNA Damage and Mutagenicity

Frank Seiler, Bernd Rehn, S. Rehn, Martina Hermann, and Joachim Bruch

Institute of Hygiene and Occupational Medicine, University of Essen Medical School; IBE, Institut für Entwicklung von Verfahren zur biologischen Emissionsbewertung, Essen; Squarix Biotechnology GmbH, Marl; Laboratorium für Toxikologie und Ökologie, Stockhausen GmbH und Co.KG, Krefeld, Germany

Exposure to quartz and high concentrations of other poorly soluble particles can lead to the development of lung tumors in the rat. The mechanisms involved in particle-induced carcinogenesis seem to include inflammation-associated production of reactive oxygen species (ROS) and DNA damage. ROS induce 8-oxoguanine (8-oxoGua) and a panel of other oxidation products in DNA. In proliferating cells such DNA lesions can lead to various types of mutations, which might be critical for cancer-related genes with respect to tumor formation. Quartz is known to mediate the induction of 8-oxoGua in the nuclear DNA of lung cells when applied to the lung of rats. We have investigated the time- and dose-dependent biologic effects of quartz and, as a control, corundum, on cell proliferation and various pulmonary inflammation and toxicity markers in rat bronchoalveolar lavage fluid (BALF); on the induction of 8-oxoGua in the DNA of rat lung cells; and on the cellular levels of p53 wild-type and p53 mutant (mut) protein. Rats were exposed by intratracheal instillation to various amounts of quartz (0.3, 1.5, or 7.5 mg/rat) or corundum (0.3, 1.5, or 7.5 mg/rat) and measured at Days 7, 21, and 90 after exposure. Corundum had no adverse effects except a slight elevation of 8-oxoGua at a dose of 7.5 mg/rat. However, significant changes in the BALF were detected at all quartz doses. 8-oxoGua was significantly increased only at 1.5 and 7.5 mg quartz/rat. The amount of cells with detectable p53 wild-type protein levels was increased at 1.5 and 7.5 mg quartz/rat at 7 and 21 d. Elevated amounts of cells with enhanced p53 mut protein levels were measured at all time points after instillation of 7.5 mg quartz/rat.

Abbreviations: bronchoalveolar lavage, BAL; BAL fluid, BALF; bromodeoxyuridine, BrdU; bovine serum albumin, BSA; 4,6-diamidino-2-phenylindole, DAPI; immunocytologic assay, ICA; mutant, mut; 8-oxoguanine, 8-oxoGua; phosphate-buffered saline, PBS; reactive oxygen species, ROS; room temperature, RT; standard deviation, SD; tumor necrosis factor, TNF.




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