胡维, 王姝, 于海兵, 丁元林. 磷酸三苯酯致大鼠肝脏代谢紊乱的生物信息学分析[J]. 环境与职业医学, 2020, 37(2): 111-120. DOI: 10.13213/j.cnki.jeom.2020.19501
引用本文: 胡维, 王姝, 于海兵, 丁元林. 磷酸三苯酯致大鼠肝脏代谢紊乱的生物信息学分析[J]. 环境与职业医学, 2020, 37(2): 111-120. DOI: 10.13213/j.cnki.jeom.2020.19501
HU Wei, WANG Shu, YU Hai-bing, DING Yuan-lin. Bioinformatic analysis on hepatic metabolic disorders induced by triphenyl phosphate[J]. Journal of Environmental and Occupational Medicine, 2020, 37(2): 111-120. DOI: 10.13213/j.cnki.jeom.2020.19501
Citation: HU Wei, WANG Shu, YU Hai-bing, DING Yuan-lin. Bioinformatic analysis on hepatic metabolic disorders induced by triphenyl phosphate[J]. Journal of Environmental and Occupational Medicine, 2020, 37(2): 111-120. DOI: 10.13213/j.cnki.jeom.2020.19501

磷酸三苯酯致大鼠肝脏代谢紊乱的生物信息学分析

Bioinformatic analysis on hepatic metabolic disorders induced by triphenyl phosphate

  • 摘要: 背景

    磷酸三苯酯(TPHP)是目前应用最广泛的有机磷酸酯类阻燃剂之一,已在多种环境介质中被检测到。由于该化合物的多重毒性,近年来TPHP的健康风险引起了广泛的关注。然而,有关TPHP暴露对肝脏代谢影响的研究较少。

    目的

    基于转录组测序数据,采用生物信息学方法探讨TPHP暴露对大鼠肝脏代谢紊乱的效应。

    方法

    基于基因表达数据库(GEO)获得基因表达谱数据集。采用主成分分析和层次聚类分析方法,依据不同剂量组的基因表达模式的相似程度将样本归类至对照组(0mg·kg-1,含5个样本)、低剂量组(55.0、110.0、220.0mg·kg-1,含9个样本)和高剂量组(441.0、881.0mg·kg-1,含6个样本);利用R 3.5.3软件中limma包筛选差异表达基因(DEGs)。运用clusterProfiler包对DEGs进行基因本体(GO)、京都基因和基因组数据库(KEGG)富集分析。利用STRING网络数据库建立蛋白质-蛋白质相互作用(PPI)网络,并运用Cytoscape 3.7.1软件的网络分析插件CytoHubba筛选中心基因。最后,运用clusterProfiler包对重要的中心基因进行基因集富集分析(GSEA)。

    结果

    与对照组相比,低剂量组DEGs共53个,其中表达上调的基因30个,表达下调的基因23个;而高剂量组DEGs共151个,其中表达上调的基因80个,表达下调的基因71个。GO和KEGG富集分析显示,两个剂量组与对照组的DEGs富集的功能相似,主要涉及昼夜节律、碳水化合物代谢、脂质代谢、氨基酸代谢、过氧化物酶体增殖物激活受体(PPAR)信号通路等生物学途径。PPI网络分析和GSEA显示,Arntl基因是唯一一个在低、高剂量组PPI网络中都存在的中心基因,Arntl基因低表达、高表达组分别在6、19条通路上富集,并且其高表达富集于不饱和脂肪酸的生物合成、PPAR信号通路等生物学途径。

    结论

    TPHP可诱导大鼠肝脏中昼夜节律、碳水化合物、脂质和氨基酸代谢途径受到干扰。节律基因Arntl可能在TPHP暴露导致的肝脏代谢紊乱中发挥重要作用,并影响内分泌功能。

     

    Abstract: Background

    Triphenyl phosphate (TPHP) is one of the most widely used organophosphate flame retardants and has been detected in a variety of environmental media. Due to its multiple toxicities, the human health risks of TPHP have attracted much attention in recent years. However, few studies have been done on the effects of TPHP exposure on liver metabolism.

    Objective

    Bioinformatic methods are used to investigate the hepatic metabolic disorders of rats exposed to different doses of TPHP based on transcriptome sequencing data.

    Methods

    Gene expression profile datasets were obtained from Gene Expression Omnibus (GEO) database. Principal component analysis and hierarchical clustering analysis were used to classify the samples into control group (0 mg·kg-1, including 5 samples), low dose group (55.0, 110.0, and 220.0 mg·kg-1, including 9 samples), and high dose group (441.0 and 881.0 mg·kg-1, including 6 samples) according to the similarity of gene expression patterns in different dose groups. Differentially expressed genes (DEGs) were screened using the limma package in R 3.5.3 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were performed by clusterProfiler package. Protein-protein interaction (PPI) network was established using STRING network database, and central genes were screened by a network analysis plug-in CytoHubba in Cytoscape 3.7.1 software. Finally, gene enrichment analysis (GSEA) was performed on the central genes using clusterProfiler package.

    Results

    Compared with the control group, there were 53 DEGs in the low dose group, including 30 up-regulated genes and 23 downregulated genes, and there were 151 DEGs in the high dose group, including 80 up-regulated genes and 71 down-regulated genes. The results of GO and KEGG enrichment analyses showed that the functions of DEGs enriching in the two dose groups were similar to those in the control group, mainly involving biological pathways such as circadian rhythm, carbohydrate metabolism, lipid metabolism, amino acid metabolism, and peroxisome proliferator-activated receptors (PPRA) signaling pathway. The results of PPI network analysis and GSEA showed that Arntl was the only gene presenting in the PPI networks of both low and high dose groups, enriching in 6 and 19 pathways of low and high expression groups respectively, and its high expression enriched in biosynthesis of unsaturated fatty acid, PPAR signaling pathway, and other biological pathways.

    Conclusion

    TPHP could induce disruption of circadian rhythm, carbohydrate, lipid, and amino acid metabolic pathways in the liver of rats. Arntl, a rhythmic gene, may play an important role in hepatic metabolic disorder induced by TPHP exposure and in affecting endocrine function.

     

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