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Posted: Nov 25, 2011
Genotoxic mode of action of fine and ultrafine dusts in lungs
(Nanowerk News) This project aimed at studying local genotoxicity of fine and ultrafine particles in lung epithelial cells by evaluating the current literature and by using an immunohistochemical approach on existing lung tissue samples from (nano)particle-exposed animals.
Local genotoxicity was assessed by applying immunhistochemical detection and subsequent quantification of different markers for DNA damage in lung tissue samples from a study previously conducted at Fraunhofer ITEM.
In this study rats were exposed intratracheally for 3 months to 3 x 2 mg crystalline silica (DQ12, 1300 nm), 3 x 2 mg amorphous silica (Aerosil® 150, 14 nm), or 3 x 6 mg carbon black (PRINTEX® 90, 14 nm). Furthermore, a carcinogenicity study with intratracheal instillation of the same particles (but different particle doses) was available at Fraunhofer ITEM. In parallel, 3-month data concerning bronchoalveolar lavage (BAL) and histological data on inflammation existed allowing correlation of genotoxicity marker expression with the outcome of this carcinogenicity study and with alterations in the lung after 3 month of exposure, respectively. The following genotoxicity markers were selected: Poly(ADP-Ribose) (PAR), phosphorylated H2AX (γ-H2AX), 8-hydroxy-2'-deoxyguanosine (8-OH-dG), and 8-oxoguanine DNA glycosylase (OGG1). PAR indicates early cellular reaction to DNA damage, γ-H2AX DNA double strand breaks (DSB), 8-OH-dG a specific oxidative DNA-base modification (one of several existing), and OGG1 repair capacity related to oxidative damage.
For quartz DQ12 all biomarkers gave statistically significant positive results, indicating profound genotoxic stress, occurrence of DSB, and oxidative DNA damage with subsequent repair activity. The response was less pronounced for PRINTEX® 90 (carbon black), but significant increase in DSB, 8-OH-dG, and OGG1-positive cytoplasm were detected. Finally, for Aerosil® 150 (amorphous silica), only 8-OH-dG levels and repair activity of oxidative DNA damage, as represented by OGG1 expression in the cytoplasm, were statistically significant. The marker which was most sensitive, differentiated best between the three particles, and correlated well with the carcinogenicity data was γ-H2AX. 8-OH-dG correlated best with the inflammation score. The findings also generally correlated with positive or negative results in the in vitro and in vivo literature data on genotoxicity of these three particles and with carcinogenicity data.
In conclusion, this study demonstrated that using immunohistochemical detection and quantification of different genotoxicity markers in lung tissue samples could be a promising approach for testing local genotoxicity and the genotoxic modes of action of particles in the lung.