来曲唑缓释片皮下给药构建小鼠多囊卵巢综合征模型及其肝脏转录组学分析

doi:10.12300/j.issn.1674-5817.2024.186

实验动物与比较医学 ›› 2025, Vol. 45 ›› Issue (2): 119-129.DOI: 10.12300/j.issn.1674-5817.2024.186

• 人类疾病动物模型 • 下一篇

来曲唑缓释片皮下给药构建小鼠多囊卵巢综合征模型及其肝脏转录组学分析

许秋雨¹, 严国锋², 付丽², 范文华², 周晶², 朱莲², 仇淑雯¹, 张洁¹, 吴铃¹()()

^1.上海交通大学医学院附属第九人民医院辅助生殖科, 上海 200011
^2.上海交通大学医学院实验动物科学部, 上海 200025

收稿日期:2024-12-17 修回日期:2025-02-06 出版日期:2025-04-25 发布日期:2025-04-25
通讯作者: 吴铃（1985—），女，博士，副主任技师，研究方向：生殖内分泌的基础和临床研究。E-mail：wuling9hospital@126.com。ORCID： 0000-0001-9217-9412
作者简介:许秋雨（2000—），女，硕士研究生，研究方向：生殖内分泌。E-mail：xqy1047817@163.com
基金资助:
国家自然科学基金资助项目“父代抗生素过度使用增加子代肥胖风险的作用和机制研究”(82171685)

A Mouse Model of Polycystic Ovary Syndrome Established Through Subcutaneous Administration of Letrozole Sustained-Release Pellets and Hepatic Transcriptome Analysis

XU Qiuyu¹, YAN Guofeng², FU Li², FAN Wenhua², ZHOU Jing², ZHU Lian², QIU Shuwen¹, ZHANG Jie¹, WU Ling¹()()

^1.Department of Assisted Reproduction, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
^2.Department of Laboratory Animal Science, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China

Received:2024-12-17 Revised:2025-02-06 Published:2025-04-25 Online:2025-04-25
Contact: WU Ling (ORCID: 0000-0001-9217-9412), E-mail: wuling9hospital@126.com

摘要/Abstract

摘要：

目的通过对青春期前小鼠进行来曲唑缓释片皮下给药和高脂饮食处理，构建小鼠多囊卵巢综合征（polycystic ovary syndrome，PCOS）模型，比较模型小鼠与安慰剂对照小鼠的肝脏转录组差异，以探索PCOS发病过程中肝脏的作用机制。方法定制剂量为2 mg的来曲唑缓释片，缓释周期为 40 d。分别将对照安慰剂缓释片和来曲唑缓释片包埋在3～4周龄的C57BL/6J小鼠颈后皮下，每组8只，构建对照组及来曲唑诱导的PCOS模型，并在包埋次日给予小鼠高脂饮食处理。造模周期5周，每周监测每组小鼠的体重和24 h进食量。收样时记录小鼠肝脏重量，通过HE染色观察小鼠卵巢和肝脏组织病理变化，通过油红O染色观察肝脏脂质沉积水平，通过F4/80免疫组织化学染色观察肝脏巨噬细胞浸润程度，通过Masson染色观察肝脏纤维化水平；通过转录组学测序技术分析对照组和模型组小鼠肝脏组织中基因表达的差异，并对显著差异表达的基因进行富集分析；通过实时荧光定量PCR验证两组小鼠肝脏组织中显著差异表达的基因。结果与对照组相比，来曲唑缓释片皮下给药和高脂饮食处理后的模型组小鼠体重显著增加（P<0.001），卵巢的多囊样表型显著，肝重比显著下降（P<0.05），但小鼠的肝脏重量、肝组织形态和脂质沉积没有显著影响（P>0.05）。转录组学测序发现，来曲唑处理后小鼠肝脏中有119个上调、217个下调的差异表达基因，广泛参与胆固醇和类固醇合成、类固醇激素合成及炎症反应相关通路。荧光定量PCR结果显示，与对照组相比，模型组小鼠肝脏的HSD3B2和HMGCR基因的mRNA表达上调（P<0.01），IL4、CCL2和COL1A1基因的mRNA 表达下调（P<0.05）。但Masson染色与F4/80免疫组织化学染色未见肝脏纤维化水平与巨噬细胞浸润程度的显著改变。结论来曲唑缓释片皮下给药和高脂饮食处理可以成功构建小鼠PCOS模型。模型小鼠肝脏中基因表达变化显著，可能通过调控胆固醇和类固醇代谢，参与PCOS的发病机制。

关键词: 来曲唑, 多囊卵巢综合征, 肝脏, 转录组测序, 小鼠

Abstract:

Objective Prepubertal mice are administered subcutaneously with letrozole sustained-release pellets behind the neck and treated with a high-fat diet to establish a mouse model of polycystic ovary syndrome (PCOS). The liver transcriptomes of the model mice are compared with those of the placebo control mice to investigate the underlying mechanisms of liver involvement in the pathogenesis of PCOS. Methods A customized 2 mg dose of letrozole sustained-release pellets with a 40-day release period was used. The control placebo and letrozole pellets were implanted subcutaneously in the dorsal cervical region of 3-4-week-old C57BL/6J mice (8 mice per group) to establish the control group and letrozole-induced PCOS model group. Both groups were treated with a high-fat diet starting the day after administration. The modeling period lasted for 5 weeks, during which body weight and 24-hour food intake were monitored in each group every week. When samples were collected, liver weight was recorded. Pathological changes in ovarian and hepatic tissues were examined by hematoxylin-eosin (HE) staining, while hepatic lipid deposition was observed by Oil Red O staining. The extent of macrophage infiltration in the liver was evaluated via F4/80 immunohistochemical staining, and hepatic fibrosis levels were observed by Masson's trichrome staining. Transcriptomic sequencing was performed to analyze differentially expressed genes (DEGs) in liver tissues between the control and model groups, followed by enrichment analysis of significant DEGs. Quantitative real-time fluorescent quantitative PCR (qPCR) was subsequently used to validate the expression of significant DEGs in liver tissues of both groups. Results Compared with the control group, the model group which received subcutaneous letrozole sustained-release pellets combined with a high-fat diet exhibited significantly increased body weight (P<0.001), prominent polycystic ovarian morphology, and significantly decreased liver-to-body weight ratio (P<0.05). However, no significant changes were observed in absolute liver weight (P>0.05), hepatic histomorphology, or lipid deposition. Transcriptome sequencing identified 119 upregulated and 217 downregulated DEGs in the liver tissues of letrozole-treated mice, which were predominantly enriched in pathways related to cholesterol and steroid biosynthesis, steroid hormone metabolism, and inflammatory responses. qPCR validation demonstrated that mRNA expression of HSD3B2 and HMGCR was significantly upregulated in liver (P<0.01), while mRNA expression of IL4, CCL2 and COL1A1 was downregulated (P<0.05) in the model group compared with the control group. However, Masson's trichrome staining and F4/80 immunohistochemical analysis showed no significant changes in hepatic fibrosis or macrophage infiltration. Conclusion Subcutaneous administration of letrozole sustained-release pellets combined with a high-fat diet successfully establishes a mouse model of PCOS. The model mice exhibited significant changes in hepatic gene expression. Liver may contribute to PCOS pathogenesis through regulating cholesterol and steroid metabolism.

Key words: Letrozole, Polycystic ovary syndrome, Liver, Transcriptome sequencing, Mice

中图分类号:

Q95-33

许秋雨,严国锋,付丽,等. 来曲唑缓释片皮下给药构建小鼠多囊卵巢综合征模型及其肝脏转录组学分析[J]. 实验动物与比较医学, 2025, 45(2): 119-129. DOI: 10.12300/j.issn.1674-5817.2024.186.

XU Qiuyu,YAN Guofeng,FU Li,et al. A Mouse Model of Polycystic Ovary Syndrome Established Through Subcutaneous Administration of Letrozole Sustained-Release Pellets and Hepatic Transcriptome Analysis[J]. Laboratory Animal and Comparative Medicine, 2025, 45(2): 119-129. DOI: 10.12300/j.issn.1674-5817.2024.186.

图/表 6

表 1 引物序列

Table 1 Sequences of primers

引物名称 Primer name	引物序列 Sequence (5'→3')
36B4-F	AGATTCGGGATATGCTGTTGGC
36B4-R	TCGGGTCCTAGACCAGTGTTC
HSD3B2-F	GGTTTTTGGGGCAGAGGATCA
HSD3B2-R	GGTACTGGGTGTCAAGAATGTCT
HMGCR-F	CAAACATTGTCACCGCCATC
HMGCR-R	CCACCCACCGTTCCTATCTC
IL4-F	GGTCTCAACCCCCAGCTAGT
IL4-R	GCCGATGATCTCTCTCAAGTGAT
CCL2-F	TTAAAAACCTGGATCGGAACCAA
CCL2-R	GCATTAGCTTCAGATTTACGGGT
COL1A1-F	GCTCCTCTTAGGGGCCACT
COL1A1-R	CCACGTCTCACCATTGGGG

图 1 来曲唑和高脂饮食造模对小鼠体重、摄食量和肝脏的影响注：A，与初始体重相比，小鼠前4 周每周体重变化率；B，小鼠造模期间每周24 h摄食量；C，小鼠卵巢HE染色（×50）；D，小鼠肝脏重量；E，小鼠肝重比；F，小鼠肝脏HE染色（×400）；G，小鼠肝脏油红O染色（×400）。每组8只小鼠；与安慰剂组相比，*P<0.05，***P<0.001，nsP>0.05。C、F和G图中，上图与下图分别代表两个独立的生物学重复实验。

Figure 1 Effects of letrozole and high-fat diet modeling on body weight， food intake and liver in miceNote： A， Weekly rate of body weight change of mice during the first 4 weeks compared to their initial body weight； B， Weekly food intake of mice in 24 hours during the modeling period； C， Ovary HE staining of mice （×50）； D， Liver weight of mice； E， Liver-to-body weight ratio of mice； F， Liver HE staining of mice （×400）； G， Liver Oil Red O staining of mice （×400）. Each group consisted of 8 mice. Compared with placebo group， *P<0.05， ***P<0.001， nsP>0.05. In fig. C， F and G， the upper and lower panels show two independent biological replicates.

图 2 来曲唑和高脂饮食造模后小鼠肝脏组织中差异基因分析注：A，来曲唑造模组 vs 安慰剂对照组的差异表达基因数量柱状图；B，来曲唑造模组 vs 安慰剂对照组的差异表达基因火山图。

Figure 2 Analysis of differentially expressed genes in liver of mice after letrozole and high-fat diet modelingNote：A， Bar chart of the number of differentially expressed genes between the letrozole model group and the placebo control group； B， Volcano plot of differentially expressed genes between the letrozole model group and the placebo control group.

图 3 来曲唑和高脂饮食造模后小鼠差异表达基因的功能注释和富集分析注：A，来曲唑造模组上调表达基因的代表性GO功能注释；B，来曲唑造模组上调表达基因的代表性KEGG富集分析；C，来曲唑造模组下调表达基因的代表性GO功能注释；D，来曲唑造模组下调表达基因的代表性 KEGG 富集分析。

Figure 3 Functional annotation and enrichment analysis of differentially expressed genes in mice after letrozole and high-fat diet modelingNote： A， Representative GO functional annotations of upregulated differentially expressed genes in the letrozole model group compared to the placebo control group； B， Representative KEGG enrichment analysis of upregulated differentially expressed genes in the letrozole model group compared to the placebo control group； C， Representative GO functional annotations of downregulated differentially expressed genes in the letrozole model group compared to the placebo control group； D， Representative KEGG enrichment analysis of downregulated differentially expressed genes in the letrozole model group compared to the placebo control group.

图 4 来曲唑和高脂饮食造模后差异表达基因的GSEA 富集分析注：A~B，来曲唑造模组 vs 安慰剂对照组GSEA富集分析（A，高表达基因集；B，低表达基因集）。FDR，假发现率。

Figure 4 GSEA enrichment analysis of differentially expressed genes after letrozole and high-fat diet modelingNote： A-B， GSEA enrichment analysis of genes in the letrozole model group compared to the placebo control group （A，upregulated gene sets； B， downregulated gene sets）. FDR， False discovery rate.

图 5 来曲唑和高脂饮食造模后小鼠差异基因的实时定量PCR验证注：A，3β-羟类固醇脱氢酶2（HSD3B2）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）基因的相对表达量；B，白细胞介素-4（IL4）、C-C基序趋化因子配体2（CCL2）、I型胶原α链（COL1A1）基因相对表达量；C，肝脏Masson染色（×400）；D，肝脏F4/80免疫组织化学染色（×400）。每组 8 只小鼠；与安慰剂对照组相比，*P<0.05，**P<0.01。C和D图中，上图与下图分别代表两个独立的生物学重复。

Figure 5 Real-time quantitative PCR verification of differentially expressed genes in mice after letrozole and high-fat diet modelingNote： A， Relative expression levels of 3 beta- and steroid delta-isomerase 2 （HSD3B2） and 3-hydroxy-3-methylglutaryl-coenzyme A reductase （HMGCR）； B， Relative expression levels of interleukin-4 （IL4），C-C motif chemokine ligand 2 （CCL2）， and collagen， type I， alpha 1 （COL1A1）； C，Liver Masson staining （×400）； D， Liver F4/80 immunohistochemistry staining （×400）. Each group consisted of 8 mice. Compared with placebo group， *P<0.05， **P<0.01. In fig. C-D， the upper and lower panels show two independent biological replicates.

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A Mouse Model of Polycystic Ovary Syndrome Established Through Subcutaneous Administration of Letrozole Sustained-Release Pellets and Hepatic Transcriptome Analysis

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