Abstract
BackgroundLittle is known about the mechanism underlying the genotoxicity observed in the liver following pulmonary exposure to carbon black (CB) nanoparticles (NPs). The genotoxicity could be caused by the presence of translocated particles or by circulating inflammatory mediators released during pulmonary inflammation and acute-phase response. To address this, we evaluated induction of pulmonary inflammation, pulmonary and hepatic acute-phase response and genotoxicity following exposure to titanium dioxide (TiO2), cerium oxide (CeO2) or CB NPs. Female C57BL/6 mice were exposed by intratracheal instillation, intravenous injection or oral gavage to a single dose of 162 μg NPs/mouse and terminated 1, 28 or 180 days post-exposure alongside vehicle control.ResultsLiver DNA damage assessed by the Comet Assay was observed after intravenous injection and intratracheal instillation of CB NPs but not after exposure to TiO2 or CeO2. Intratracheal exposure to NPs resulted in pulmonary inflammation in terms of increased neutrophils influx for all NPs 1 and 28 days post-exposure. Persistent pulmonary acute phase response was detected for all NPs at all three time points while only a transient induction of hepatic acute phase response was observed. All 3 materials were detected in the liver by enhanced darkfield microscopy up to 180 days post-exposure. In contrast to TiO2 and CeO2 NPs, CB NPs generated ROS in an acellular assay.ConclusionsOur results suggest that the observed hepatic DNA damage following intravenous and intratracheal dosing with CB NPs was caused by the presence of translocated, ROS-generating, particles detected in the liver rather than by the secondary effects of pulmonary inflammation or hepatic acute phase response.
Highlights
Little is known about the mechanism underlying the genotoxicity observed in the liver following pulmonary exposure to carbon black (CB) nanoparticles (NPs)
bronchoalveolar lavage (BAL) fluid cellular composition Analysis of BAL fluid cellular composition following pulmonary exposure to the NPs revealed that intratracheal instillation of all three particles resulted in increased numbers of total cell counts after day 1 as well as increased neutrophil influx in lungs 1 and 28 days postexposure (Fig. 2 and Table 2)
In the present work, we wanted to determine whether the observed hepatic DNA strand breaks following pulmonary exposure to CB NPs were caused by primary genotoxicity due to the direct effects of translocated particles and their ability to induce reactive oxygen species formation [21] or by secondary genotoxicity caused by pulmonary inflammation and acute phase response triggering molecular signaling cascade that, in turn, initiate downstream toxic effects in the liver [41, 42]
Summary
Little is known about the mechanism underlying the genotoxicity observed in the liver following pulmonary exposure to carbon black (CB) nanoparticles (NPs). The genotoxicity could be caused by the presence of translocated particles or by circulating inflammatory mediators released during pulmonary inflammation and acute-phase response. Inhalation and intratracheal instillation of NPs induce pulmonary inflammation which is accompanied by a Modrzynska et al Particle and Fibre Toxicology (2018) 15:2 pulmonary acute phase response [13,14,15]. Secondary genotoxicity refers to DNA damage as a result of action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) as well as other secondary mediators (cytokines, chemokines) that are generated during particle-induced inflammation and acute phase response in the lungs that could initiate DNA damaging processes in the liver including induction of a hepatic acute phase response [19, 20]
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