The formation of secondary organic aerosols (SOA) by atmospheric oxidation reactions substantially contributes to the burden of fine particulate matter (PM2.5), which has been associated with adverse health effects (e.g., cardiovascular diseases). However, the molecular and cellular effects of atmospheric aging on aerosol toxicity have not been fully elucidated, especially in model systems that enable cell-to-cell signaling. In this study, we aimed to elucidate the complexity of atmospheric aerosol toxicology by exposing a coculture model system consisting of an alveolar (A549) and an endothelial (EA.hy926) cell line seeded in a 3D orientation at the air‒liquid interface for 4 h to model aerosols. Simulation of atmospheric aging was performed on volatile biogenic (β-pinene) or anthropogenic (naphthalene) precursors of SOA condensing on soot particles. The similar physical properties for both SOA, but distinct differences in chemical composition (e.g., aromatic compounds, oxidation state, unsaturated carbonyls) enabled to determine specifically induced toxic effects of SOA. In A549 cells, exposure to naphthalene-derived SOA induced stress-related airway remodeling and an early type I immune response to a greater extent. Transcriptomic analysis of EA.hy926 cells not directly exposed to aerosol and integration with metabolome data indicated generalized systemic effects resulting from the activation of early response genes and the involvement of cardiovascular disease (CVD) -related pathways, such as the intracellular signal transduction pathway (PI3K/AKT) and pathways associated with endothelial dysfunction (iNOS; PDGF). Greater induction following anthropogenic SOA exposure might be causative for the observed secondary genotoxicity. Our findings revealed that the specific effects of SOA on directly exposed epithelial cells are highly dependent on the chemical identity, whereas non directly exposed endothelial cells exhibit more generalized systemic effects with the activation of early stress response genes and the involvement of CVD-related pathways. However, a greater correlation was made between the exposure to the anthropogenic SOA compared to the biogenic SOA. In summary, our study highlights the importance of chemical aerosol composition and the use of cell systems with cell-to-cell interplay on toxicological outcomes.

中文翻译：

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二次有机气溶胶的化学成分调节上皮内皮体外共培养中的转录组和代谢组信号传导


大气氧化反应形成的二次有机气溶胶（SOA）在很大程度上增加了细颗粒物（PM2.5）的负担，而细颗粒物与不良健康影响（例如心血管疾病）有关。然而，大气老化对气溶胶毒性的分子和细胞影响尚未完全阐明，特别是在支持细胞间信号传导的模型系统中。在这项研究中，我们旨在通过暴露一个共培养模型系统来阐明大气气溶胶毒理学的复杂性，该模型系统由肺泡 (A549) 和内皮 (EA.hy926) 细胞系组成，在气液界面以 3D 方向接种 4 h 气溶胶模型。对凝结在烟灰颗粒上的 SOA 的挥发性生物源（β-蒎烯）或人为（萘）前体进行了大气老化模拟。两种 SOA 具有相似的物理性质，但化学成分（例如芳香族化合物、氧化态、不饱和羰基）存在明显差异，从而能够确定 SOA 特异性诱导的毒性作用。在 A549 细胞中，接触萘衍生的 SOA 在更大程度上诱导了应激相关的气道重塑和早期 I 型免疫反应。对未直接暴露于气溶胶​​的 EA.hy926 细胞进行转录组分析，并与代谢组数据整合，表明早期反应基因的激活和心血管疾病 (CVD) 相关途径（例如细胞内信号转导途径）的参与导致了全身性影响。 PI3K/AKT）和与内皮功能障碍相关的通路（iNOS；PDGF）。人为 SOA 暴露后的更大诱导可能是观察到的继发遗传毒性的原因。 我们的研究结果表明，SOA 对直接暴露的上皮细胞的具体影响高度依赖于化学特性，而非直接暴露的内皮细胞则通过早期应激反应基因的激活和 CVD 相关途径的参与表现出更普遍的系统效应。然而，与生物 SOA 相比，人为 SOA 暴露之间存在更大的相关性。总之，我们的研究强调了化学气溶胶成分的重要性以及使用细胞系统与细胞间相互作用对毒理学结果的重要性。