A transcriptomic analysis of acute hepatotoxicity induced by aristolochic acid Ⅰ in mice

Gerui ZHU; Jing WANG; Kai HUANG; Yuan PENG; Chenghai LIU; Yanyan TAO

doi:10.3969/j.issn.1001-5256.2021.10.026

Volume 37 Issue 10

Oct. 2021

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A transcriptomic analysis of acute hepatotoxicity induced by aristolochic acid Ⅰ in mice

DOI: 10.3969/j.issn.1001-5256.2021.10.026

1.
Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2.
Shanghai Key Laboratory of Traditional Chinese Medicine, Shanghai 201203, China

Research funding:

The Special Project for Significant New Drug Research and Development in the Major National Science and Technology Projects of China (2019ZX09201001);

The Science and Technology Innovation Action Plan of the Shanghai Municipal Science and Technology Commission (19401901500);

The Three-Year Action Plan of for the Development of TCM in Shanghai (ZY-[2018-2020]-CCCX-5001)

Received Date: 2021-03-04
Accepted Date: 2021-05-13
Published Date: 2021-10-20

Abstract

Abstract

Objective To investigate the molecular mechanism of aristolochic acid Ⅰ (AAⅠ) inducing acute hepatotoxicity in mice. Methods A total of 15 male C57BL/6 mice were randomly divided into normal group with 6 mice and treatment group with 9 mice. The mice in the treatment group were given intraperitoneal injection of AAⅠ at a dose of 20 mg/kg for 5 consecutive days and were sacrificed to collect samples on day 6. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured, and HE staining was used to observe liver histological changes; three liver tissue samples were randomly selected from each group, and RNA was extracted for high-throughput transcriptome sequencing. Bioinformatics analysis and functional prediction were used to screen out differentially expressed genes, and quantitative real-time PCR (qRT-PCR) was used for validation. The t-test was used for comparison of continuous data between two groups. Results Compared with the normal group, the treatment group had significant increases in the activities of ALT and AST (t=4.331 and 4.947, both P < 0.01), as well as disordered structure of hepatic lobules and spotted necrosis in hepatic lobules shown by HE staining. A total of 1352 differentially expressed genes were obtained based on the screening conditions of logFC > 2 and P < 0.05, among which there were 703 upregulated genes and 649 downregulated genes. The GO and KEGG enrichment analyses of these differentially expressed genes showed significant enrichment in GO terms (such as small molecular catabolism, immune response involving neutrophils, cytoplasmic vesicle lumen in secretory granules, cytoplasmic vesicle lumen, extracellular structural organization, and extracellular matrix) and KEGG pathways (such as chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, steroid hormone biosynthesis, transcriptional dysregulation in cancer, protein digestion and absorption, regulation of TRP channel by inflammatory mediators, drug metabolism, complement and coagulation cascade, glutathione metabolism, and the PPAR signaling pathway). A cluster analysis (P < 0.05) showed that significantly downregulated genes included Srd5a1, Lipc, Aqp8, Hba-a1, Slco1a1, and Pklr, which were validated by qRT-PCR (all P < 0.05). Conclusion AA Ⅰ can lead to significant acute hepatotoxicity, which mainly involves the processes such as chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, steroid hormone biosynthesis, and transcriptional dysregulation in cancer.
- ARISTOLOCHIC ACID,
- Transcriptome,
- Chemical and Drug Induced Liver Injury,
- Mice, Inbred C57BL

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References

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A transcriptomic analysis of acute hepatotoxicity induced by aristolochic acid Ⅰ in mice

DOI: 10.3969/j.issn.1001-5256.2021.10.026