In contrast, all other dusts enhanced expression of OGG1 only in cytoplasm but not in nuclei. For the interpretation of the results for OGG1 it is important to know that OGG1 is constitutively expressed and can be induced as well as reduced in lung cells by toxic insults, as for example by cadmium (Potts et al., 2003). This repression phenomenon

this website was observed in the early phase after intratracheal instillation of diesel exhaust particles, which contain a carbon black nucleus, in the lungs of Fisher 344 rats (Tsurudome et al., 1999), rendering OGG1 a genotoxicity marker that is difficult to interpret. Nevertheless, OGG1 expression correlated with the inflammation score, but this was significant only when comparing identical animals and for the cytoplasmic localization. Similar to PAR, OGG1 expression in both nuclei and cytoplasm showed no correlation with cell death markers in BAL, but like 8-OH-dG correlated with the respective tumor induction pattern. In summary, OGG1 is an interesting marker to confirm inflammation and oxidative stress and to

investigate mechanistic aspects concerning induction of intracellular oxidative stress by particles. However, it seems to be less suited to directly differentiate the genotoxic potential of different materials at high particle doses. Our retrospective investigation was performed learn more using lung tissue samples of rats exposed to high particle doses. The primary goal of the original study being to induce marked inflammation in the lung, only one dose

level per particle type was investigated, and this dose level was not uniform for all test items. Consequently, we know nothing about dose response and it is difficult to compare the genotoxic potential of the three particle types. With respect to risk assessment and further validation of the methodological approach, it would thus be desirable to evaluate in a future study more than one dose level, including very low dose levels to be able to analyze whether genotoxicity also occurs at dose levels where no inflammation Florfenicol can be detected. Despite these limitations, the obtained data allow some mechanistic conclusions and judgments concerning the genotoxic potential of the different particles. Secondary inflammation-driven genotoxic events were recently postulated as principal mechanism of the carcinogenic action of crystalline silica (Borm et al., 2011). Our study supports this hypothesis. The highly significant correlations of genotoxicity marker expression and inflammation score when comparing on an individual-animal basis indicate that lung inflammation and thus a secondary mechanism of genotoxicity is involved in particle-induced DNA damage. The pre-mutagenic oxidative DNA lesion 8-OH-dG and the corresponding repair protein OGG1 in the cytoplasm exhibited highly significant correlation rates with the histopathologic inflammation score when analyzing individual animal data.