同种异体子宫内膜异位症大鼠模型用于GnRH激动剂类药物的药效评价研究

doi:10.12300/j.issn.1674-5817.2023.150

实验动物与比较医学 ›› 2024, Vol. 44 ›› Issue (2): 127-138.DOI: 10.12300/j.issn.1674-5817.2023.150

• 人类疾病动物模型 • 下一篇

同种异体子宫内膜异位症大鼠模型用于GnRH激动剂类药物的药效评价研究

钟瑞华¹, 李国停¹, 杨文捷¹, 郭湘洁¹, 周洁芸¹, 胡颖怡¹, 倪其承¹^,², 杨野¹^,², 张敏³, 朱焰¹()()

^1.国家卫生健康委员会生育调节药械重点实验室, 上海生殖健康药具工程技术研究中心, 上海市生物医药技术研究院生殖药理组, 上海 200237
^2.复旦大学药学院, 上海 200032
^3.长春金赛药业有限公司, 长春 130012

收稿日期:2023-11-03 修回日期:2024-02-01 出版日期:2024-04-25 发布日期:2024-04-25
通讯作者: 朱焰（1970—），女，博士，研究员，从事生殖药理学研究。E-mail： zhuyan@sippr.org。ORCID： 0000-0001-5136-7601
作者简介:钟瑞华（1988—），女，硕士，助理研究员，从事生殖药理学研究。E-mail： zrh8804@126.com

Application of Allograft Endometriosis Rat Model in Pharmaco-dynamic Evaluation of GnRH Agonists

Ruihua ZHONG¹, Guoting LI¹, Wenjie YANG¹, Xiangjie GUO¹, Jieyun ZHOU¹, Yingyi HU¹, Qicheng NI¹^,², Ye YANG¹^,², Min ZHANG³, Yan ZHU¹()()

^1.NHC Key Laboratory of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies Laboratory of Reproductive Pharmacology, Shanghai 200237, China
^2.Pharmacy School, Fudan University, Shanghai 200032, China
^3.Changchun Gene Science Pharmaceutical Co. , Ltd. , Changchun 130012, China

Received:2023-11-03 Revised:2024-02-01 Published:2024-04-25 Online:2024-04-25
Correspondence to: ZHU Yan (ORCID:0000-0001-5136-7601), E-mail: zhuyan@sippr.org

摘要/Abstract

摘要：

目的用同种异体移植的方法构建大鼠子宫内膜异位症模型，并评价促性腺激素释放激素（gonadotropin-releasing hormone，GnRH）激动剂GenSci006对实验大鼠子宫内膜异位症模型的影响。方法取供体SPF级雌性SD大鼠的子宫内膜移植于受体雌性大鼠的腹腔壁上，构建同种异体的子宫内膜异位症模型。3周后，测量异位内膜的长、宽、高，计算给药前异位内膜的体积V₁。将进行假手术操作的大鼠设为假手术组，将造模大鼠随机分为模型组、曲普瑞林组（0.25 mg/kg）、GenSci006-1组（0.125 mg/kg）和GenSci006-2组（0.25 mg/kg）共4组，每组大鼠16只。各组大鼠单次给予相应的药物，假手术组和模型组给予同等体积的溶剂。3周后，再次测量异位内膜，计算给药后异位内膜的体积V₂和抑制率；通过比较脏器系数及病理切片的变化，判断GenSci006 对大鼠子宫和卵巢组织的影响；ELISA法测定血清中雌二醇（estradiol，E₂）、孕酮（progesterone，P₄）、卵泡刺激素（follicle stimulating hormone，FSH）和黄体生成素（luteinizing hormone，LH）水平的变化；实时荧光定量PCR法测定下丘脑和垂体中GnRH受体（GnRH receptor，GnRHR）mRNA的表达水平。蛋白质印迹法检测异位内膜组织中雌激素受体（estrogen receptor，ER）α、ERβ和孕激素受体（progesterone receptor，PR）蛋白的表达。结果给药3周后发现，与模型组相比，曲普瑞林组和GenSci006-2组大鼠的体重显著增加（P<0.05），而异位内膜的体积显著减小（P<0.05）。与假手术组相比，模型组子宫、卵巢脏器系数及子宫内膜厚度无明显变化（P>0.05）；与模型组相比，曲普瑞林组和GenSci006-2组子宫脏器系数及子宫内膜厚度显著降低（P<0.05）。与假手术组相比，模型组血清中E₂、P₄、FSH、LH水平无明显变化（P>0.05）；与模型组相比，曲普瑞林组、GenSci006-1组和GenSci006-2组大鼠的卵巢脏器系数和血清P₄水平均显著降低（P<0.05），而GenSci006-1组大鼠的血清LH水平明显升高（P<0.05），但各组血清E₂和FSH水平并无显著变化（P>0.05）。与模型组相比，曲普瑞林组和GenSci006-2组大鼠垂体GnRHR mRNA表达水平显著下调（P<0.05）；各组大鼠下丘脑组织中GnRHR mRNA表达及异位内膜组织中ERα、ERβ、PR蛋白表达水平无明显变化（P>0.05）。结论大鼠同种异体子宫内膜异位症模型适宜作为筛选和评价子宫内膜异位症治疗药物的动物模型，而且异位内膜体积、抑制率、子宫及卵巢脏器系数、血清E₂水平均可作为检测药物疗效的指标。

关键词: 子宫内膜异位症, GenSci006, 曲普瑞林, 异位内膜, 大鼠

Abstract:

Objective To establish an allogeneic rat model of endometriosis and to evaluate the effects of gonadotropin-releasing hormone (GnRH) agonist GenSci006 on experimental rat endometriosis. Methods Endometrium from SPF grade donor female SD rats were transplanted onto the abdominal wall of recipient female rats to construct an allogeneic endometriosis model. The rats undergoing sham surgery were divided into the sham group. Three weeks later, the length, width and height of the ectopic endometrium were measured, and the volume of the endometrium (V₁) was calculated before drug administration. The modeling rats were randomly divided into four groups: model group, triptorelin group (0.25 mg/kg), GenSci006-1 group (0.125 mg/kg) and GenSci006-2 group (0.25 mg/kg). Each group had 16 rats and received a single dose of the corresponding drug. The sham group and model group were administered an equal volume of solvent. Three weeks after administration, ectopic endometrium was measured to calculate the volume V₂ and inhibition rate. The effect of GenSci006 on rat uterus and ovarian tissues was assessed by comparing organ coefficients and changes in pathological sections. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of serum estradiol (E₂), progesterone (P₄), follicle stimulating hormone (FSH), and luteinizing hormone (LH). Real-time fluorescent quantitative PCR was used to detect the expression of GnRH receptor (GnRHR) mRNA in the hypothalamus and pituitary. Western blot was used to detect the expression of estradiol receptor alpha (ERα), beta (ERβ) and progesterone receptor (PR) in ectopic endometrium. Results Three weeks after administration, compared with the model group, the body weight of rats in the triptorelin and GenSci006-2 groups significantly increased (P < 0.05), while the volume of ectopic endometrium significantly decreased (P < 0.05). Compared with the sham group, the model group showed no significant changes in uterine and ovarian organ coefficients or endometrial thickness (P > 0.05). Compared with the model group, the uterine organ coefficients and endometrial thickness were significantly reduced in the triptorelin and GenSci006-2 groups (P < 0.05). Compared with the sham group, the serum levels of E₂, P₄, FSH and LH in the model group showed no significant changes (P > 0.05). Compared with the model group, the ovarian organ coefficient and serum P₄ levels of rats in the Triptorelin, GenSci006-1, and GenSci006-2 groups were significantly reduced (P < 0.05), while the serum LH levels of rats in the GenSci006-1 group were significantly increased (P < 0.05). However, there were no significant changes in serum E₂ and FSH levels in each group (P > 0.05). Compared with the model group, the expression levels of GnRHR mRNA in the pituitary tissue of rats in the triptorelin and GenSci006-2 groups were significantly downregulated (P < 0.05), with no significantly changes in the hypothalamus (P > 0.05). There were no significant changes in the expression level of GnRHR mRNA in the hypothalamus or the protein levels of ERα, ERβ and PR in the ectopic endometrial tissue in any group (P > 0.05). Conclusion The allogeneic endometriosis rat model is a suitable animal model for screening and evaluating drugs for treating endometriosis. The volume of ectopic endometrium, inhibition rate, uterine and ovarian organ coefficients, and serum E₂ levels may serve as indicators for detecting drug efficacy.

Key words: Endometriosis, GenSci006, Triptorelin, Ectopic endometrium, Rat

中图分类号:

R-332

钟瑞华,李国停,杨文捷,等. 同种异体子宫内膜异位症大鼠模型用于GnRH激动剂类药物的药效评价研究[J]. 实验动物与比较医学, 2024, 44(2): 127-138. DOI: 10.12300/j.issn.1674-5817.2023.150.

Ruihua ZHONG,Guoting LI,Wenjie YANG,et al. Application of Allograft Endometriosis Rat Model in Pharmaco-dynamic Evaluation of GnRH Agonists[J]. Laboratory Animal and Comparative Medicine, 2024, 44(2): 127-138. DOI: 10.12300/j.issn.1674-5817.2023.150.

图/表 6

注：Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。
">

图1 GenSci006对同种异体移植子宫异位内膜症模型大鼠体重的影响
注：Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。

Figure 1 Effect of GenSci006 on body weight of allograft endometriosis rat model
Note：Sham group （n=16）， transplanted with fat tissues around the uterus and injected with GenSci006 specific solvent； Model group （n=16）， xenografted with endometrial tissues and injected with GenSci006 specific solvent； Triptorelin group（n=16）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=16）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively. Compared with the model group， ^*P<0.05.

注：A，给药前各组大鼠的异位内膜图片；B，给药后各组大鼠的异位内膜图片；C，给药3周后各组大鼠的异位内膜病理学特征（HE染色，×10）；D，给药前、后各组大鼠的异位内膜体积及抑制率。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。
">

图2 GenSci006对同种异体移植子宫内膜异位症模型大鼠异位内膜的抑制作用
注：A，给药前各组大鼠的异位内膜图片；B，给药后各组大鼠的异位内膜图片；C，给药3周后各组大鼠的异位内膜病理学特征（HE染色，×10）；D，给药前、后各组大鼠的异位内膜体积及抑制率。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。

Figure 2 Inhibitory effect of GenSci006 on ectopic endometrium in allograft endometriosis rats
Note： A， Pictures of ectopic endometrium before administration； B， Pictures of ectopic endometrium after administration；C， Pathological section of ectopic endometrium in endometriosis model rats（HE staining， ×10）；D， Tthe volume of ectopic endometrium before and after administration and the inhibition rate. Sham group （n=16）， transplanted with fat tissues around the uterus and injected with GenSci006 specific solvent； Model group （n=16）， xenografted with endometrial tissues and injected with GenSci006 specific solvent； Triptorelin group （n=16）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=16）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively. Compared with the model group，^*P<0.05.

注：A示子宫组织病理切片（×10）；B示卵巢组织病理切片（×10），箭头所指处为生长卵泡；C示子宫、卵巢脏器系数和子宫组织的内膜厚度。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。
">

图3 GenSci006对同种异体移植子宫内膜异位症模型大鼠子宫和卵巢的影响
注：A示子宫组织病理切片（×10）；B示卵巢组织病理切片（×10），箭头所指处为生长卵泡；C示子宫、卵巢脏器系数和子宫组织的内膜厚度。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组16只大鼠；与模型组相比，^*P<0.05。

Figure 3 Effect of GenSci006 on uterus and ovary in allograft endometriosis rats
Note：A， Pathological section of uterus in endometriosis model rats （HE staining， ×10）；B， Ppathological section of ovary in endometriosis model rats （HE staining， ×10）； The arrow represents growth follicles；C， The coefficient of uterine organs，endometrial thickness and ovarian organ coefficient. Sham group （n=16）， transplanted with fat tissues around the uterus and injected with GenSci006 specific solvent； Model group （n=16）， xenografted with endometrial tissues and injected with GenSci006 specific solvent； Triptorelin group （n=16）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=16）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively. Compared with the model group，^*P<0.05

注：A，血清中雌二醇（E₂）水平；B，血清中孕酮（P₄）水平；C，血清中卵泡刺激素（FSH）水平；D，血清中黄体生成素（LH）水平。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组8只大鼠；与模型组相比，^*P<0.05；与曲普瑞林组相比，^#P<0.05。
">

图 4 GenSci006对同种异体移植子宫内膜异位症模型大鼠血清E₂、P₄、FSH和LH水平的影响
注：A，血清中雌二醇（E₂）水平；B，血清中孕酮（P₄）水平；C，血清中卵泡刺激素（FSH）水平；D，血清中黄体生成素（LH）水平。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组8只大鼠；与模型组相比，^*P<0.05；与曲普瑞林组相比，^#P<0.05。

Figure 4 Effect of GenSci006 on serum levels of E₂， P₄， FSH and LH in allograft endometriosis rats
Note： A， Serum level of estradiol （E₂）； B， Serum level of progesterone （P₄）； C， Serum level of follicle stimulating hormone （FSH）； D， Serum level of luteinizing hormone （LH）. Sham group （n=8）， transplanted with fat tissues and injected with GenSci006 specific solvent； Model group （n=8）， xenografted with endometrial tissues around the uterus and injected with GenSci006 specific solvent； Triptorelin group （n=8）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=8）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively. Compared with the model group， ^*P<0.05； Compared with the triptorelin group， ^#P<0.05.

注：A，下丘脑组织中促性腺激素释放激素受体（GnRHR） mRNA 表达；B，垂体组织中GnRHR mRNA 表达。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组6只大鼠；与模型组相比，^*P<0.05。
">

图5 GenSci006对同种异体移植子宫内膜异位症模型大鼠下丘脑和垂体组织中GnRHR基因mRNA表达水平的影响
注：A，下丘脑组织中促性腺激素释放激素受体（GnRHR） mRNA 表达；B，垂体组织中GnRHR mRNA 表达。Sham即假手术组，移植同种异体子宫周围的脂肪到大鼠腹壁，然后注射GenSci006专用溶剂；Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组6只大鼠；与模型组相比，^*P<0.05。

Figure 5 Effect of GenSci006 on GnRHR mRNA expression in hypothalamus and pituitary of allograft endometriosis rats
Note： A， Gonadotropin-releasing hormone receptor （GnRHR） mRNA expression in hypothalamus； B， GnRHR mRNA expression in pituitary. Sham group （n=6）， transplanted with fat tissues and injected with GenSci006 specific solvent； Model group （n=6）， xenografted with endometrial tissues around the uterus and injected with GenSci006 specific solvent； Triptorelin group （n=6）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=6）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively. Compared with the model group， ^*P<0.05.

注：ERα/β，雌激素受体α/β；PR，孕激素受体。Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组6只大鼠。
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图6 GenSci006对同种异体移植子宫内膜异位症模型大鼠异位内膜组织中ERα、ERβ、PR蛋白表达的影响
注：ERα/β，雌激素受体α/β；PR，孕激素受体。Model即模型组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射GenSci006专用溶剂；Triptorelin即曲普瑞林组，移植同种异体子宫内膜组织到大鼠腹壁，然后注射曲普瑞林0.25 mg/kg；GenSci006-1和GenSci006-2组，移植同种异体子宫内膜组织到大鼠腹壁，然后分别注射0.125 mg/kg和 0.25 mg/kg的GenSci006。每组6只大鼠。

Figure 6 Effect of GenSci006 on protein expression of ERα、ERβ、PR in ectopic endometrial tissues of allograft endometriosis rat model
Note： ERα/β， Estradiol receptor α/β； PR， Progesterone receptor. Model group （n=6）， xenografted with endometrial tissues around the uterus and injected with GenSci006 specific solvent； Triptorelin group （n=6）， xenografted with endometrial tissues and injected with 0.25 mg/kg triptorelin； GenSci006-1 and GenSci006-2 groups （each n=6）， xenografted with endometrial tissues and injected with 0.125 mg/kg and 0.25 mg/kg GenSci006， respectively.

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同种异体子宫内膜异位症大鼠模型用于GnRH激动剂类药物的药效评价研究

Application of Allograft Endometriosis Rat Model in Pharmaco-dynamic Evaluation of GnRH Agonists

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