基于转录组测序方法研究加替沙星对小鼠的肝损伤作用

doi:10.3969/j.issn.1004-616x.2022.01.004

癌变·畸变·突变 ›› 2022, Vol. 34 ›› Issue (1): 20-24.doi: 10.3969/j.issn.1004-616x.2022.01.004

基于转录组测序方法研究加替沙星对小鼠的肝损伤作用

国瑞贤^1,3, 谢广云², 韩莹³

1. 中央民族大学药学院, 北京 100081;
2. 中国疾病预防控制中心职业卫生与中毒控制所, 北京 100050;
3. 中国食品药品检定研究院化学药品检定所抗生素室, 北京 102629

收稿日期:2021-08-24 修回日期:2021-11-15 出版日期:2022-01-31 发布日期:2022-02-15
通讯作者: 谢广云,E-mail:guangyunxie@163.com;韩莹,E-mail:yinghan@nifdc.org.cn E-mail:guangyunxie@163.com;yinghan@nifdc.org.cn
作者简介:国瑞贤,E-mail:15931796879@163.com
基金资助:
国家“重大新药创制”科技重大专项资助项目（2017ZX09101001-007-003）

Injury effects of gatifloxacin in livers of mice based on transcriptome sequencing

GUO Ruixian^1,3, XIE Guangyun², HAN Ying³

1. School of Pharmacy, Minzu University of China, Beijing 100081;
2. Nationnal Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050;
3. Division of Antibiotics, Institute for Chemical Drug Control, National Institutes for Food and Drug Control, Beijing 102629, China

Received:2021-08-24 Revised:2021-11-15 Online:2022-01-31 Published:2022-02-15

摘要/Abstract

摘要： 目的： 探讨加替沙星（GAT）对小鼠肝脏的损伤作用及其机制。方法： 选取32只SPF级雄性昆明小鼠作为研究对象，随机分为4组：低、中、高剂量（分别为25、50、100 mg/kg） GAT组和对照组。给药体积按10 mL/kg，连续灌胃给药7 d，对照组给予对应体积的生理盐水。通过检测各组小鼠血清中的谷丙转氨酶（ALT）、谷草转氨酶（AST）、碱性磷酸酶（AKP）、肌酐（CRE）和甘油三酯（TG）浓度，初步评价加替沙星导致的小鼠肝组织损伤。进一步利用转录组测序技术检测各组小鼠肝脏的基因表达谱，筛选差异表达基因，对差异基因进行基因本体论（GO）功能分类，并采用京都基因与基因组百科全书（KEGG）数据库进行信号通路富集分析。结果： 与对照组比较，高剂量GAT组小鼠肝脏质量显著降低（P<0.01）；低、中剂量GAT组肝脏系数显著降低（P<0.01）；低、中剂量GAT组小鼠血清ALT浓度显著降低（P<0.05或0.01）；低剂量GAT组小鼠血清AST浓度显著降低（P<0.01）。与对照组比较，中剂量GAT组共筛选出27个差异表达基因（包括20个上调基因，7个下调基因）。GO功能分类提示这些基因主要富集在免疫系统、多细胞生物、多生物及生殖过程等17个生物过程中。KEGG通路分析提示差异基因主要富集于脂质代谢、萜类化合物和聚酮化合物的代谢等22条通路中。结论： GAT可导致小鼠肝功能发生变化，并通过影响小鼠肝脏内胆汁酸和胆固醇等内分泌系统和脂质代谢等的平衡，造成肝组织损伤。

关键词: 加替沙星, 肝毒性, 转录组学, 差异表达基因, 小鼠

Abstract: OBJECTIVE: To investigate the injury effects of gatifloxacin in livers of mice and its possible mechanisms of action. METHODS: Thirty-two SPF male Kunming mice were selected as the research objects and randomly divided into 4 groups:normal (saline),low-dose (25 mg/kg),medium-dose (50 mg/kg) and high-dose (100 mg/kg). The administration volume was 10 mL/kg,and the intragastric administration was continued for 7 days. The normal group was given the corresponding volume of normal saline. Through the detection of alanine aminotransferase (ALT),aspartate aminotransferase (AST),alkaline phosphatase (AKP),creatinine (CRE) and triglyceride (TG) in the serum of each group of mice, the preliminary data indicated that gatifloxacin caused damage to liver tissues in mice. Therefore,the transcriptome sequencing technology was used to detect gene expression profiles in livers from each group,to screen differentially expressed genes,and to perform gene ontology (GO) functional classification of differential genes and Kyoto encyclopedia of genes and genomes (KEGG) signal pathway enrichment analysis. RESULTS: Compared with the normal group,the qualities of the livers from the high-dose group were significantly reduced (P<0.01),and the liver coefficients for the low- and medium-dose groups were significantly reduced (P<0.01). The serum ALT levels from the high-dose group were significantly reduced (P<0.01);the serum AST levels from the middle and high-dose groups were significantly reduced (P<0.01). Compared with the normal group,a total of 27 differentially expressed genes (including 20 up-regulated genes and 7 down-regulated genes) were screened out in the medium-dose group. GO functional classifications suggest that these genes were mainly enriched in 17 biological processes including the immune system,multicellular organisms,and multibiological processes. KEGG pathway analyses indicate that the differential genes were mainly enriched in 22 pathways including lipid metabolism,terpenoids and polyketide metabolism. CONCLUSION: Gatifloxacin caused alterations in liver functions of mice by affecting the balance of endocrine system such as bile acid and cholesterol and lipid metabolism in the liver of mice.

Key words: gatifloxacin, hepatotoxicity, transcriptomics, differentially expressed genes, mice

中图分类号:

R965.3

国瑞贤, 谢广云, 韩莹. 基于转录组测序方法研究加替沙星对小鼠的肝损伤作用[J]. 癌变·畸变·突变, 2022, 34(1): 20-24.

GUO Ruixian, XIE Guangyun, HAN Ying. Injury effects of gatifloxacin in livers of mice based on transcriptome sequencing[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(1): 20-24.

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基于转录组测序方法研究加替沙星对小鼠的肝损伤作用

Injury effects of gatifloxacin in livers of mice based on transcriptome sequencing

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