Bioinformatic analysis on hepatic metabolic disorders induced by triphenyl phosphate

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.