Nanoparticle-driven DNA damage mimics irradiation-related carcinogenesis pathways

Abstract

The epidemiological association between cancer and exposure to ambient air pollution particles (particles with a 50% cut-off aerodynamic diameter of 10 mm (PM10)) has been related to the ability of PM10 and its constituent nanoparticles (NPs) to cause reactive oxidative species (ROS)-driven DNA damage. However, there are no data on the molecular response to these genotoxic effects.In order to assess whether PM10, NP and ROS-driven DNA damage induce carcinogenesis pathways, A549 cells were treated with tert-butyl-hyperperoxide (Tbh), urban dust (UD), carbon black (CB), nanoparticulate CB (NPCB), benzo(a)pyrene (BaP) and NPCB coated with BaP for f24 h. Single-and double-strand breakage of DNA was determined by comet assay; cell cycle status was analysed using flow cytometry. Nuclear extracts or acid-extracted histones were used for Western blot analysis of p-ser15-p53 (p53 phosphorylated at ser15), p53 binding protein (53BP) 1, phospho-histone H2A.X (p-H2A.X) and phospho-BRCA1 (p-BRCA1).UD caused both single-and double-strand DNA breaks, while other tested NPs caused only single-strand DNA breaks. NPs significantly altered cell cycle kinetics. Tbh enhanced p-H2A.X after 1 and 6 h (2.1-and 2.2-fold, respectively). NP increased 53BP1 expression at 1 h (2.4-8.7-fold) and p-BRCA1 at 1-6 h. N-acetylcysteine blocked NP-driven p-ser15-p53 response.In conclusion, nanoparticles and reactive oxidative species induce DNA damage, activating p53 and proteins related to DNA repair, mimicking irradiation-related carcinogenesis pathways.KEYWORDS: DNA damage, H2A.X histone, nanoparticles, particles with a 50% cut-off aerodynamic diameter of 10 mm, reactive oxidative species I ncreased exposures to particles with a 50% cut-off aerodynamic diameter of 10 mm (PM10) is associated with an increased risk of cardiovascular and respiratory deaths and hospital admissions, as well as lung cancer [1,2]. Direct evidence of DNA damage caused by PM10 has also been confirmed [3]. Attention has focused on the PM10 in cities because that is where most deaths occur, where pollution is routinely monitored and hence the associations are best seen. Typical urban PM10 is comprised of f50% by mass of combustion-derived nanoparticles (CDNPs; particles ,100 nm), which are carbon-centred particles, typically from automobile engine exhausts, with associated compounds including transition metals, ammonium salts of nitrogen, sulphur and chlorine plus geological dust and organic matter [4]. Many toxicological studies over the last decade have confirmed that CDNPs readily generate oxidative stress through reactive oxidative species (ROS) and inflammation and nanoparticles (NPs) are seen as the most harmful components of the PM10 mix [5][6][7].Several investigators have shown that oxidative stress may play a major role in particle-induced DNA damage, which can be prevented by antioxidants and scavengers of ROS [8]. However, detailed molecular mechanisms involved in the hallmark cellular responses to genotoxic effects are currently not known, in contras...

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