Joint Mass Spectrometry Center (JMSC) at Comprehensive Molecular Analytics (CMA), Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.
Joint Mass Spectrometry Center (JMSC) at Analytical Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Str. 27, D-18059, Rostock, Germany.
Part Fibre Toxicol. 2024 Sep 19;21(1):38. doi: 10.1186/s12989-024-00600-x.
The formation of secondary organic aerosols (SOA) by atmospheric oxidation reactions substantially contributes to the burden of fine particulate matter (PM), 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.
大气氧化反应形成的次生有机气溶胶（SOA）大大增加了细颗粒物（PM）的负担，而 PM 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，尤其是在能够进行细胞间信号传递的模型系统中。
在这项研究中，我们旨在通过暴露于肺泡（A549）和内皮（EA.hy926）细胞系的共培养模型系统来阐明大气气溶胶毒理学的复杂性，该模型系统以 3D 方向接种在气液界面上 4 小时以模拟气溶胶。挥发性生物源（β-蒎烯）或人为源（萘）SOA 前体在烟尘颗粒上凝结，对其进行大气老化模拟。这两种 SOA 的物理性质相似，但化学组成（例如芳香族化合物、氧化态、不饱和羰基）存在明显差异，因此能够确定 SOA 具体诱导的毒性作用。
在 A549 细胞中，暴露于萘衍生的 SOA 会更大程度地诱导与应激相关的气道重塑和早期 I 型免疫反应。未直接暴露于气溶胶的 EA.hy926 细胞的转录组分析以及与代谢组数据的整合表明，由于早期反应基因的激活以及与心血管疾病（CVD）相关途径的参与，会产生全身性效应，例如细胞内信号转导途径（PI3K/AKT）和与内皮功能障碍相关的途径（iNOS；PDGF）。人为 SOA 暴露后更大的诱导可能是观察到的二次遗传毒性的原因。
我们的研究结果表明，SOA 对直接暴露的上皮细胞的特定影响高度依赖于化学特性，而未直接暴露的内皮细胞则表现出更广泛的全身性效应，表现为早期应激反应基因的激活和与 CVD 相关途径的参与。然而，与生物源 SOA 相比，人为 SOA 的暴露具有更大的相关性。总之，我们的研究强调了气溶胶化学组成以及使用具有细胞间相互作用的细胞系统对毒理学结果的重要性。
