Particularly harmful particles? : a study of airborne particles with a focus on genotoxicity and oxidative stress

Detta är en avhandling från Stockholm : Karolinska Institutet, Biosciences and Nutrition

Sammanfattning: Today it is well established that particulate matter (PM) cause a wide range of health effects. The underlying mechanisms likely include inflammation, oxidative stress and genotoxicity. There is however a lack of knowledge regarding how particles from different sources contribute to these effects. Furthermore, oxidative stress is difficult to analyse due to the risk of artificial oxidation during sample preparation and analysis. The main aims of this thesis were to investigate different methods for analysis of oxidative DNA damage and to compare the ability of particles from different source to a) cause DNA damage, b) cause oxidation of DNA, c) induce inflammatory mediators, d) cause mitochondrial depolarisation and c) form intracellular reactive oxygen species (ROS). In Paper I and II the background level of oxidative DNA damage in human lymphocytes was investigated. HPLC (high performance liquid chromatography) with electrochemical detection was used to analyse 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG) and the Comet assay in combination with the enzyme formamidopyrimidine glycosylase (FPG) was used to detect mainly oxidised purines. It was found that the level in a healthy Swedish population was around 1 8-oxodG per 106 dG measured using HPLCEC, and 0.24 FPG sites per 106 dG using the Comet assay. Furthermore, there was no correlation between the levels of 8-oxodG and FPG sites. In Papers III-VI, the toxicity of particles from different sources were studied. It was found that subway particles were most genotoxic of all particles tested and that they caused formation of 8-oxodG and intracellular ROS in cultured human lung cells. In contrast, the street particles caused the highest release of inflammatory cytokines. Particles from tire-road wear collected using a road-simulator were genotoxic and induced inflammatory cytokines without involvement of particles related to vehicle exhaust. Furthermore, more efficient combustion of wood and pellet gave much less emissions of particles, but those emitted did not show less toxicity. Finally, diesel particles were most potent to cause mitochondrial damage, followed by PM from wood combustion and the subway. In conclusion, PM from different sources showed different types of toxic effects. Subway particles were most potent regarding genotoxicity and oxidative stress in vitro, the main focus in this thesis, and may in this context therefore be regarded as "particularly harmful".

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