State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China; State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China.
Environ Pollut. 2019 Mar;246:45-52. doi: 10.1016/j.envpol.2018.11.108. Epub 2018 Dec 1.
Exposure to airborne particulate matter (PM) induced various adverse health effects, such as metabolic syndrome, systemic inflammation and respiratory infection. However, a global influence of PM-induced metabolic and proteomic disorders remains confusing, and the underlying mechanism is still under-explored. Herein, LC-MS/MS-based metabolomics, lipidomics and isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics were applied to analyze the toxicological characteristics of PM from Taiyuan City in China (Taiyuan-PM) on human lung carcinoma cells (A549) after the 24-h treatment. Metabolites, lipids and proteins that have distinctive differences were screened by SIEVE, LipidSearch and Proteome Discoverer, respectively. The abundance of 56 metabolites (40 increased and 16 decreased), 22 lipids (19 increased and 3 decreased) and 81 proteins (55 up-regulated and 26 down-regulated) were significantly changed upon the PM treatment. Among the proteomics analysis, 16 proteins were specifically related to RNA splicing, mainly including up-regulated serine/arginine-rich splicing factor 1 (SRSF1), SRSF2, small nuclear ribonucleoprotein 70 kDa (snRNP70), small nuclear ribonucleoprotein polypeptide B (SNRPB), SNRPC, SNRPE and down-regulated heterogeneous nuclear ribonucleoprotein U-like 2 (hnRNP UL2). At the metabolic level, PM exposure significantly altered the sphingolipid metabolism, including ceramide, serine, sphingosine and sphingomyelin. It was proposed that excessive accumulation of ceramide and expression of key enzymes (ceramide synthases, phingomyelinase, sphingosine kinase types 2 and protein phosphatase-1) induced the secretion of pro-inflammatory cytokines, generation of lipotoxicity and alterations of RNA splicing in PM-treated A549 cells. In general, our results demonstrated that ceramide accumulation and altered RNA splicing could becritical contributors to PM-induced cytotoxicity at metabolic and proteomic level, which might be considered as potential markers for toxicological evaluation of PM samples.
空气中颗粒物（PM）的暴露会引起各种不良健康影响，如代谢综合征、全身炎症和呼吸道感染。然而，PM 引起的代谢和蛋白质组紊乱的全球影响仍然令人困惑，其潜在机制仍未得到充分探索。在此，我们采用基于 LC-MS/MS 的代谢组学、基于等重标记相对和绝对定量（iTRAQ）的蛋白质组学方法，分析了来自中国太原市（太原-PM）的 PM 对人肺癌细胞（A549）在 24 小时处理后的毒理学特征。通过 SIEVE、LipidSearch 和 Proteome Discoverer 分别筛选出具有显著差异的代谢物、脂质和蛋白质。PM 处理后，56 种代谢物（40 种增加，16 种减少）、22 种脂质（19 种增加，3 种减少）和 81 种蛋白质（55 种上调，26 种下调）的丰度发生了显著变化。在蛋白质组学分析中，有 16 种蛋白质与 RNA 剪接特别相关，主要包括上调的丝氨酸/精氨酸丰富剪接因子 1（SRSF1）、SRSF2、小核核糖核蛋白 70kDa（snRNP70）、小核核糖核蛋白 B（SNRPB）、SNRPC、SNRPE 和下调的异质核核糖核蛋白 U 样 2（hnRNP UL2）。在代谢水平上，PM 暴露显著改变了神经酰胺、丝氨酸、神经鞘氨醇和神经鞘磷脂的鞘脂代谢。研究表明，神经酰胺的过度积累和关键酶（神经酰胺合酶、神经鞘磷脂酶、神经鞘氨醇激酶 2 型和蛋白磷酸酶 1）的表达，诱导了促炎细胞因子的分泌、脂毒性的产生和 PM 处理的 A549 细胞中 RNA 剪接的改变。总的来说，我们的结果表明，神经酰胺的积累和 RNA 剪接的改变可能是 PM 诱导细胞毒性在代谢和蛋白质组学水平上的关键因素，它们可能被认为是 PM 样本毒理学评价的潜在标志物。
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