DNA Damage and Inflammation in the Rat Quartz Model: Differences in Inflammatory Response and Formation of Oxidative DNA Adducts to High and Low Dose of DQ12 Quartz

Abstract

Chronic exposure to poorly soluble particles such as quartz and diesel soot produces dose-dependent inflammatory responses in the rat lung. It has been shown that the inflammation in the rat lung causes persistent oxidative DNA damage and mutations in proliferation-competent cells, which are thought to be critical for tumorigenesis. In measuring various inflammatory parameters to a multidose quartz exposure in parallel with the amount of 8-oxoguanine (8-oxoGua) on the cellular level in rat lung, mechanistic data for understanding the underlying processes could be gained. Rat lungs (female Wistar, 180–220 g/bodyweight) were instilled with quartz DQ12 (doses 0.3, 1.5, and 7.5 mg/animal; controls: corundum at the same doses and physiological NaCl) and analyzed 90 days after intratracheal instillation. The bronchoalveolar lavage (BAL) fluid was determined for inflammation markers (differential cell count, protein, lung surfactant lipids, and tumor necrosis factor alpha); tissue sections of lungs were investigated for the amount of 8-oxoGua on the cellular level using an antibody against 8-oxoGua. The results reflect different responses for quartz versus all controls and show a clear dose-response relationship. Quartz elicited inflammatory reponses determined in the BAL fluid even at the low dose (0.3 mg/animal). In contrast, the level of 8-oxoGua in the lung of animals exposed to 0.3 mg quartz was not statistically increased above controls, whereas doses of 1.5 mg and 7.5 mg caused significant elevations. The data obtained indicate a no-effect level for the persistence of the mutagenic DNA adduct 8-oxoguanine in the epithelial lung cells at a low-dose quartz exposure that is still inflammatoric and fibrogenic.