FORMATION AND PERSISTENCE OF 8-OXOGUANINE IN RAT LUNG-CELLS AS AN IMPORTANT DETERMINANT FOR TUMOR-FORMATION FOLLOWING PARTICLE EXPOSURE

Exposure of rats to quartz (or various other particles) can lead to th e development of lung tumors. At the moment, the mechanisms involved i n particle-induced tumor formation are not clarified. However, it is s uggested that inflammation, in conjunction with the production of reac tive oxygen species (ROS) and an enhancement of epithelial cell prolif eration, may pay a key role in the development of lung tumors, ROS ind uces 8-oxoguanine (8-oxoGua) and other mutagenic DNA oxidation product s, which can be converted to mutations in proliferating cells. Mutatio n formation in cancer-related genes is a critical event with respect t o 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 sal ine or left untreated. Measurements were carried out 7, 21, and 90 day s after the exposures. 8-oxoGua levels were determined in lung tissue sections at the single cell level by immunocytological assay using a r abbit anti-8-oxoGua antibody. After exposure to quartz, 8-oxoGua level s were significantly increased at all time points of investigation. Ad ditionally, we observed inflammation and an enhanced cell proliferatio n. Exposure to corundum had no adverse effects on the lung; neither in creased 8-oxoGua levels nor enhanced cell proliferation or inflammatio n were detected. These observations support the suggestion that inflam mation associated with increased 8-oxoGua levels in lung cells and inc ;eased cell proliferation is an important determinant for particle-ind uced development of lung tumors in the rat.