Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; College of Environmental Science and Engineering, Tongji University, Shanghai, China.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Environ Pollut. 2021 Jul 1;280:116951. doi: 10.1016/j.envpol.2021.116951. Epub 2021 Mar 19.
Nitrate is a major pollutant component in ambient PM. It is known that chronic exposure to PM NO damages respiratory functions. We aim to explore the underlying toxicological mechanism at single cell resolution.
We systematically conducted exposure experiments on forty C57BL/6 mice, assessed respiratory functions, and profiled lung transcriptome. . Afterward, we estimated the cell type compositions from RNA-seq data using deconvolution analysis. The genes and pathways associated with respiratory function and dysregulated by to PM NO exposure were characterized at bulk-tissue and single-cell resolution.
PM NO exposure did not significantly modify the cell type composition in lung, but profoundly altered the gene expression within each cell type. At ambient concentration (22 μg/m), exposure significantly (FDR<10%) altered 95 genes' expression. Among the genes associated with respiratory functions, a large fraction (74.6-91.7%) were significantly perturbed by PM NO exposure. For example, among the 764 genes associated with peak expiratory flow (PEF), 608 (79.6%) were affected by exposure (p = 1.92e-345). Pathways known to play role in lung disease pathogenesis, including circadian rhythms, sphingolipid metabolism, immune response and lysosome, were found significantly associated with respiratory functions and disrupted by PM NO exposure.
This study extended our knowledge of PM NO exposure's effect to the levels of lung gene expression, pathways, lung cell type composition and cell specific transcriptome. At single cell resolution, we provided insights in toxicological mechanism of PM NO exposure and subsequent pulmonary disease risks.
硝酸盐是环境 PM 中主要的污染物成分。已知慢性暴露于 PM 中的 NO 会损害呼吸系统功能。我们旨在探索其在单细胞分辨率下的潜在毒理学机制。
我们系统地对四十只 C57BL/6 小鼠进行了暴露实验，评估了它们的呼吸功能，并对肺转录组进行了分析。之后，我们使用去卷积分析从 RNA-seq 数据中估计细胞类型组成。我们从整体组织和单细胞分辨率上对与呼吸功能相关且受 PM NO 暴露调控的基因和途径进行了表征。
PM NO 暴露并未显著改变肺中的细胞类型组成，但却显著改变了每个细胞类型内的基因表达。在环境浓度（22μg/m）下，暴露显著（FDR<10%）改变了 95 个基因的表达。在与呼吸功能相关的基因中，很大一部分（74.6-91.7%）受到 PM NO 暴露的显著影响。例如，在与呼气峰流速（PEF）相关的 764 个基因中，有 608 个（79.6%）受到了暴露的影响（p=1.92e-345）。与肺病发病机制相关的途径，包括昼夜节律、鞘脂代谢、免疫反应和溶酶体，被发现与呼吸功能显著相关，并受到 PM NO 暴露的破坏。
本研究将我们对 PM NO 暴露对肺基因表达、途径、肺细胞类型组成和细胞特异性转录组水平的影响的认识扩展到了新的领域。在单细胞分辨率下，我们提供了有关 PM NO 暴露的毒理学机制及其随后的肺部疾病风险的深入见解。
