a Institute of Environmental Health, College of Public Health , National Taiwan University , Taipei , Taiwan.
b National Museum of Marine Biology and Aquarium , Pingtung , Taiwan.
Nanotoxicology. 2018 Jun;12(5):439-452. doi: 10.1080/17435390.2018.1458918. Epub 2018 Apr 11.
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.
氧化锌 (ZnO) 的纳米和细颗粒与人类的呼吸道毒性有关，但潜在的分子机制尚不清楚。我们之前的基于核磁共振的代谢组学研究表明，呼吸系统中含有磷酸胆碱的脂质 (PC-CL) 的变化与 ZnO 颗粒引起的呼吸道毒性有关。然而，与不良反应相关的脂质种类和可能的生物标志物特征的细节尚未确定。因此，应用基于液相色谱-质谱 (LC-MS) 的脂质组学平台，通过吸入一系列浓度的纳米 (35nm) 或细颗粒 (250nm) ZnO 颗粒，检查大鼠肺部 PC-CL 种类的变化。进行主成分分析 (PCA)、偏最小二乘判别分析 (PLS-DA) 和 Mann-Whitney U (MWU) 检验与错误发现率 (FDR) 控制，以探索受到干扰的脂质种类，并在 ZnO 颗粒暴露后区分潜在的肺生物标志物特征。PCA 和 PLS-DA 模型表明，细颗粒 ZnO 颗粒处理组和高浓度纳米组与对照组以及低浓度和中浓度纳米组分离。MWU 检验的结果进一步表明，经过 FDR 调整后，许多 PC-CL 种类在高浓度和中浓度细颗粒组中发生改变。此外，我们的结果表明，在 ZnO 诱导的氧化应激和炎症反应中，涉及抗氧化、膜构象和细胞信号转导的脂质发生改变。一种脂质 PC(18:0/18:1) 在区分 ZnO 颗粒暴露与对照组方面表现出良好的区分能力 (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，还为 ZnO 颗粒暴露提供了一种脂质生物标志物。
