Environmental Health Perspectives 105, Supplement 5, September 1997

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Formation and Persistence of 8-Oxoguanine in Rat Lung Cells as an Important Determinant for Tumor Formation following Particle Exposure

Peter Nehls, 1 Frank Seiler, 1 Bernd Rehn, 1 Ruth Greferath, 2 and Joachim Bruch 1

1 Institute of Hygiene and Occupational Medicine, University of Essen Medical School, Essen, Germany
2 Center for Blood Research Laboratory, Harvard Medical School, Boston, Massachusetts

Abstract
Exposure of rats to quartz (or various other particles) can lead to the development of lung tumors. At the moment, the mechanisms involved in particle-induced tumor formation are not clarified. However, it is suggested that inflammation, in conjunction with the production of reactive oxygen species (ROS) and an enhancement of epithelial cell proliferation, may play a key role in the development of lung tumors. ROS induces 8-oxoguanine (8-oxoGua) and other mutagenic DNA oxidation products, which can be converted to mutations in proliferating cells. Mutation formation in cancer-related genes is a critical event with respect to tumor formation. In this study we investigated the effects of quartz (DQ12) and of the nontumorigenic dust corundum on the induction of 8-oxoGua in the DNA of rat lung cells, as well as on cell proliferation and pulmonary inflammation. Wistar rats were exposed by intratracheal instillation to quartz (2.5 mg/rat) or corundum (2.5 mg/rat) suspended in physiological saline; control animals exposed to physiological saline or left untreated. Measurements were carried out 7, 21, and 90 days after the exposures. 8-oxoGua levels were determined in lung tissue sections at the single cell level by immunocytological assay using a rabbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua levels were significantly increased at all time points of investigation. Additionally, we observed inflammation and an enhanced cell proliferation. Exposure to corundum had no adverse effects on the lung; neither increased 8-oxoGua levels nor enhanced cell proliferation or inflammation were detected. These observations support the suggestion that inflammation associated with increased 8-oxoGua levels in lung cells and increased cell proliferation is an important determinant for particle-induced development of lung tumors in the rat. -- Environ Health Perspect 105(Suppl 5):1291-1296 (1997)

Key words : dust, quartz, corundum, rat, inflammation, cell proliferation, 8-oxoguanine, anti-8-oxoguanine antibody, immunocytological assay

This paper is based on a presentation at The Sixth International Meeting on the Toxicology of Natural and Man-Made Fibrous and Non-Fibrous Particles held 15-18 September 1996 in Lake Placid, New York. Manuscript received at EHP 26 March 1997; accepted 14 April 1997.

R. Greferath has been a Ph.D. student with P. Nehls at the Laboratory of Molecular Biology and General Pathology, Department of Pathology, University of Ulm, Germany. This work was supported by the Minister für Wirtschaft, Mittelstand und Technologie des Landes Nordrhein-Westfalen, Arbeitsgemeinschaft Staub- und Silikosebekämpfung.

Address correspondence to Dr. P. Nehls, Institute of Hygiene and Occupational Medicine, University of Essen Medical School, Hufelandstrasse 55, 45 122 Essen, Germany. Telephone: 49 201 723-4595. Fax: 49 201 723-5911. E-mail: 100321.1427@compuserve.com

Abbreviations used: BAL, bronchoalveolar lavage; BrdUrd, bromodeoxyuridine; BSA, bovine serum albumin; 3 H-dGuo, 2´-deoxy-(1´,2´- 3 H)-guanosine; ICA, immunocytological assay; 8-oxodGuo, 7,8-dihydro-8-oxo-2´-deoxyguanosine; 8-oxoGua, 8-oxoguanine; 8-oxoGuo, 7,8-dihydro-8-oxoguanosine; PBS, phosphate-buffered saline; ROS, reactive oxygen species; TG, thyroglobulin; TNF- alpha , tumor necrosis factor alpha.

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Last Update: December 1, 1997