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

Abstract

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.

High Accumulation of Platinum-DNA Adducts in Strial Marginal Cells of the Cochlea Is an Early Event in Cisplatin but Not Carboplatin Ototoxicity

“…5B). Antibody-derived TRITC signals were nearly absent in control cells but intermediate and high in the nuclei of cells exposed to 10 or 50 mM H 2 O 2 , respectively, These results confirmed earlier findings from cell culture experiments and from in vivo studies in lung tissues of rats exposed to ROS-inducing quartz particles (Nehls et al, 1997;Seiler et al, 2001). …”

“…Despite efficient cellular repair mechanisms, this challenge leads to steady state levels of 8-oxoG lesions in the nuclear DNA of all cells. Analyses in human and in rodent tissues revealed molar ratios of approximately four 8-oxoG residues per 10 6 guanines in DNA, which translates into the presence of approximately 10.000 adducts per diploid cell (Seiler et al, 2001;Gedik and Collins, 2005). In this study, a single high-dose injection of cisplatin did not significantly increase the basal 8-oxoG levels in the DNA of marginal cells or other cochlear cells analyzed up to 48 h after exposure.…”

“…Slides with cells or tissue sections were incubated with rabbit anti-(8-oxoG) antibody (1 g of antibody/ml of PBS/1% BSA) for 16 h at 4°C. This antibody was characterized previously in various immunoassays (radioimmunoassay, enzyme-linked immunosorbent assay, ICA) for its specific binding to 8-oxoG and the sensitive detection of the DNA oxidation product in cultured cells and in lung tissue sections (Nehls et al, 1997;Seiler et al, 2001). After washing with PBS/BSA, adducts were visualized with goat anti-(rabbit Ig) F(ab) 2 fragments conjugated to tetramethylrhodamine B isothiocyanate (TRITC; 2 g/ml PBS/1% BSA; 45 min, 37°C; Dianova, Hamburg, Germany).…”

Effects from a 90-day inhalation toxicity study with cerium oxide and barium sulfate nanoparticles in rats

“…Potential genotoxic effects have been investigated for many particles, including poorly soluble, and especially those with pro-carcinogenic activity [46]. Significant increases in 8-OHdG together with changes of Ki67 levels have been described for quartz particles [47]. Correlations between the genotoxicity marker and tumor development after exposure to diesel exhaust particles has been detected by Ichinose et al [48].…”

Invited Review: Oxidation of Biological Systems: Oxidative Stress Phenomena, Antioxidants, Redox Reactions, and Methods for Their Quantification

“…Seiler et al (226) applied immunohistochemical staining for 8-OHdG on frozen lung sections and tested the time-and dose-dependent biologic effects of different doses of quartz. Morphometric analysis of the uorescent signals indicated that doses of quartz higher than 0.3 mg/day induced signi cantly increased 8-OHdG levels in lung cells, following 21 and 90 days of exposure (Figure 10 A-D).…”