Health Risk Assessment for Air Pollutants: Alterations in Lung and Cardiac Gene Expression in Mice Exposed to Milano Winter Fine Particulate Matter (PM2.5)

Oxidative stress, pulmonary and systemic inflammation, endothelial cell dysfunction, atherosclerosis and cardiac autonomic dysfunction have been linked to urban particulate matter exposure. The chemical composition of airborne pollutants in Milano is similar to those of other European cities though with a higher PM2.5 fraction. Milano winter fine particles (PM2.5win) are characterized by the presence of nitrate, organic carbon fraction, with high amount of polycyclic aromatic hydrocarbons and elements such as Pb, Al, Zn, V, Fe, Cr and others, with a negligible endotoxin presence. In BALB/c mice, we examined, at biochemical and transcriptomic levels, the adverse effects of repeated Milano PM2.5win exposure in lung and heart. We found that ET-1, Hsp70, Cyp1A1, Cyp1B1 and Hsp-70, HO-1, MPO respectively increased within lung and heart of PM2.5win-treated mice. The PM2.5win exposure had a strong impact on global gene expression of heart tissue (181 up-regulated and 178 down-regulated genes) but a lesser impact on lung tissue (14 up-regulated genes and 43 down-regulated genes). Focusing on modulated genes, in lung we found two- to three-fold changes of those genes related to polycyclic aromatic hydrocarbons exposure and calcium signalling. Within heart the most striking aspect is the twofold to threefold increase in collagen and laminin related genes as well as in genes involved in calcium signaling. The current study extends our previous findings, showing that repeated instillations of PM2.5win trigger systemic adverse effects. PM2.5win thus likely poses an acute threat primarily to susceptible people, such as the elderly and those with unrecognized coronary artery or structural heart disease. The study of genomic responses will improve understanding of disease mechanisms and enable future clinical testing of interventions against the toxic effects of air pollutant.

氧化应激、肺部与全身炎症、内皮细胞功能障碍、动脉粥样硬化以及心脏自主神经功能障碍，均与城市颗粒物暴露存在关联。米兰大气污染物的化学成分与其他欧洲城市相近，但PM2.5占比更高。米兰冬季细颗粒物（PM2.5win）以硝酸盐、有机碳组分为主要特征，同时含有大量多环芳烃及铅（Pb）、铝（Al）、锌（Zn）、钒（V）、铁（Fe）、铬（Cr）等元素，内毒素含量可忽略不计。本研究以BALB/c小鼠为对象，从生化与转录组学层面探究了反复暴露于米兰冬季细颗粒物（PM2.5win）对肺与心脏的不良影响。我们观察到，在经PM2.5win处理的小鼠肺与心脏组织中，内皮素1（Endothelin-1）、热休克蛋白70（Heat Shock Protein 70）、细胞色素P450 1A1（Cytochrome P450 1A1）、细胞色素P450 1B1（Cytochrome P450 1B1）、热休克蛋白70（Hsp-70）、血红素氧合酶1（Heme Oxygenase 1）以及髓过氧化物酶（Myeloperoxidase）的表达水平分别出现上调。PM2.5win暴露对心脏组织的全局基因表达具有显著影响（181个基因上调、178个基因下调），但对肺组织的影响相对较弱（14个基因上调、43个基因下调）。针对差异表达基因的分析显示，肺组织中与多环芳烃暴露及钙信号通路相关的基因出现了2至3倍的表达变化；而在心脏组织中，最显著的变化是胶原蛋白、层粘连蛋白相关基因以及参与钙信号通路的基因出现了2至3倍的表达上调。本研究拓展了既往研究结果，证实反复滴注PM2.5win可诱发全身性不良影响。因此，PM2.5win可能主要对易感人群构成急性威胁，例如老年人以及未被确诊的冠状动脉疾病或结构性心脏病患者。对基因组应答反应的研究，将有助于加深对疾病发病机制的理解，并为未来针对空气污染物毒性效应的干预措施开展临床试验提供支撑。