Zinc oxide (ZnO) nano- and fine-sized particles are associated with respiratory toxicity in humans, but the underlying molecular mechanisms remain unclear. Our previous nuclear magnetic resonance-based metabolomic study demonstrated that changes in phosphorylcholine-containing lipids (PC-CLs) in the respiratory system were associated with ZnO particle-induced respiratory toxicity. However, the details of the lipid species associated with adverse effects and possible biomarker signatures have not been identified. Thus, a liquid chromatography-mass spectrometry (LC-MS)-based lipidomics platform was applied to examine the alterations of PC-CL species in the lungs of rats treated with a series of concentrations of nano-sized (35 nm) or fine-sized (250 nm) ZnO particles via inhalation. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and the Mann–Whitney U (MWU) test with false discovery rate (FDR) control were conducted to explore the perturbed lipid species and to discriminate a potential pulmonary biomarker signature after ZnO particle exposure. The PCA and PLS-DA models revealed that the fine-sized ZnO particle-treated groups and the high-concentration nano-sized group were separated from the control groups as well as from the low and moderate nano-sized groups. The results from the MWU test further suggested that after FDR adjustment, numerous PC-CL species were altered in the high-concentration and moderate-concentration fine-sized groups. Furthermore, our results suggested that lipids involved in anti-oxidation, membrane conformation, and cellular signal transduction were altered in response to ZnO-induced oxidative stress and inflammation. One lipid, PC(18:0/18:1), exhibited good performance (AUC > 0.8) of discriminative ability in distinguishing ZnO particle exposure from the control. These findings not only provide a foundation for the exploration of possible ZnO particle-mediated mechanisms but also suggest a lipid biomarker for ZnO particle exposure.

中文翻译：

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基于LC-MS的脂质组学研究吸入纳米和细小ZnO颗粒后的急性大鼠肺部反应

纳米氧化锌（ZnO）和细小颗粒与人类呼吸道毒性有关，但潜在的分子机制仍不清楚。我们以前的基于核磁共振的代谢组学研究表明，呼吸系统中含磷酸胆碱的脂质（PC-CLs）的变化与ZnO颗粒诱导的呼吸道毒性有关。但是，尚未确定与不良反应和可能的生物标志物签名相关的脂质种类的详细信息。因此，基于液相色谱-质谱（LC-MS）的脂质组学平台被应用于检查用一系列浓度的纳米级（35 nm）或精细浓度的大鼠处理后的肺中PC-CL物种的变化。吸入可分离出大小为（250 nm）的ZnO颗粒。主成分分析（PCA），ü进行了具有错误发现率（FDR）对照的（MWU）测试，以探索受扰动的脂质种类，并辨别ZnO颗粒暴露后潜在的肺部生物标记物特征。PCA和PLS-DA模型显示，细颗粒ZnO颗粒处理组和高浓度纳米颗粒组与对照组以及低和中等纳米颗粒组分离。MWU测试的结果进一步表明，在调整FDR之后，高浓度和中等浓度的细粉组中的许多PC-CL种类都发生了变化。此外，我们的结果表明，参与抗氧化，膜构象和细胞信号转导的脂质响应ZnO诱导的氧化应激和炎症而改变。一种脂质PC（18：0/18：1）在区分ZnO颗粒暴露与对照时表现出良好的判别能力（AUC> 0.8）。这些发现不仅为探索可能的ZnO颗粒介导的机制提供了基础，而且还提出了ZnO颗粒暴露的脂质生物标志物。