Investigating the cardiotoxicity of particulate matter air pollution using a mouse model

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation (BHF) An estimated 4.2 million premature deaths worldwide are attributed to air pollution, primarily through increased cardiovascular (CV) morbidity and mortality. Studies have found particulate matter (PM), a subgroup of pollutants, are associated most strongly with CV disease (CVD); particularly due to the ability of smaller particles (PM2.5), such as polyaromantic hydrocarbons (PAHs), to cross the alveolar-blood barrier and enter the systemic circulation. Most research on PAHs is done in fish and there is a paucity of experimental evidence in mammalian models. Using a mouse model, this study has shown that exposure to a single PAH, Phenanthrene (Phe), can directly alter cardiac activity. Acute exposure (15 minutes) to Phe led to a significant reduction in heart rate and prolongation of the RR interval both ex-vivo (25uM Phe, 17% reduction, P=0.022, n=5) in isolated hearts and in-vivo (50ug/kg Phe, 10% reduction, P=0.0043, n=7) in anaesthetised mice, suggesting Phe has some direct effects on the heart, which are unaffected by peripheral factors. To investigate the effects of prolonged Phe exposure, wild-type mice (10-weeks) were exposed to either 30ug/kg Phe (n=7), 3ug/kg Phe (n=6) or vehicle only (DMSO, n=6) for a 28-day period, followed by in-vivo electrocardiograph and echocardiograph recordings and tissue collection. Exposure to 30ug/kg Phe had a significant impact on in-vivo HR and led to prolongation of the QTc interval (n=7, P<0.05), suggesting the pro-arrhythmic effects of Phe previously seen in fish, may also occur in mammals. Echocardiography data showed exposure to 3ug/kg Phe only significantly reduced end-diastolic volume by almost 50% (n=5, P<0.05). This data suggests Phe is also affecting the ability of the heart to fill. No significant differences in heart weight were observed between groups and molecular analysis found no changes in the RNA levels of common hypertrophic markers (ANP and BNP). Using Gas-chromatography-mass-spectrophotometry (GCMS) we found no differences in the concentration of Phe in cardiac tissue, suggesting this level of exposure does not lead to Phe accumulation. Further, more detailed molecular studies are needed to investigate the full effects of Phe and provide a mechanistic explanation for the physiological effects seen in this study. This study is the first to show that exposure to a single pollutant, Phe, can have significant effects on the mammalian cardiovascular system. This study is also the first to investigate prolonged exposure to Phe in mice, showing actions on both cardiac electrophysiology and ventricular filling. More detailed investigations of Phe exposure, both acute and chronic, in mouse models of health and disease could reveal key mechanisms of actions for common pollutants such as Phe. As the levels of pollution continue to rise worldwide, it is essential we understand the mechanisms of these pollutants, as only then can we manage and mitigate this avoidable cause of disease and death.