不同剂量环磷酰胺诱发卵巢早衰小鼠模型对衰老和凋亡的影响及机制探讨  

Effects and mechanisms of cyclophosphamide-induced premature ovarian failure in mouse models:the impact of different doses on senescence and apoptosis

作　　者：苏德慧 苏会娜 谈诚[1] 刘艳华 姜晓琳 孙晓婉 张梦雨 雷同昊 马瑞琼[1] 杨欣[1] SU Dehui;SU Huina;TAN Cheng;LIU Yanhua;JIANG Xiaolin;SUN Xiaowan;ZHANG Mengyu;LEI Tonghao;MA Ruiqiong;YANG Xin(Department of Obstetrics and Gynecology,Peking University People's Hospital,Beijing 100044,China)

机构地区：[1]北京大学人民医院妇产科,北京100044

出　　处：《中国妇产科临床杂志》2025年第2期129-133,共5页Chinese Journal of Clinical Obstetrics and Gynecology

摘　　要：目的探讨不同剂量环磷酰胺(CTX)诱发卵巢早衰(POF)小鼠模型卵巢功能变化、衰老凋亡的机制及选择最佳造模方式。方法选择6~8周龄雌性小鼠共30只,随机分为6组:对照组、POF1组(120 mg/kg)、POF2组(200 mg/kg)、POF3组(50 mg/kg×14 d)、POF4组(400 mg/kg)和POF5组(25 mg/kg×14 d),均采用CTX腹腔注射,比较不同造模剂量及给药频率下POF小鼠模型的卵巢功能及衰老、凋亡的变化。结果与正常组比较,各模型组小鼠均表现为动情周期紊乱,抗缪乐管激素(AMH)表达减少,卵巢组织纤维化加重,卵泡数减少(P<0.05),促卵泡激素受体(FSHR)表达明显降低(P<0.05),且损伤程度与CTX剂量呈正相关(|r|>0.500,P<0.05)。同时,各模型组小鼠均出现细胞衰老及细胞凋亡增加,但在POF1、2、5组中衰老相关分子如细胞周期蛋白依赖性激酶抑制剂2A(p16)、细胞周期蛋白依赖性激酶抑制剂1A(p21)、细胞衰老相关β-半乳糖苷酶(β-gal)表达显著高于POF3组(P<0.05),而在POF3组中,凋亡相关分子如B细胞淋巴瘤2相关x蛋白(Bax)、半胱氨酸天冬氨酸蛋白酶3(Caspase3)、磷酸化H2A组蛋白家族成员X(γ-H2AX)表达显著高于POF2组、POF5组(P<0.05)。结论不同剂量的CTX均可诱发卵巢早衰小鼠模型,且卵巢损伤程度呈剂量依赖式增加。较低剂量CTX模型组引起的卵巢损伤以细胞衰老为主,而较高剂量的CTX模型组引起的卵巢损伤以细胞凋亡为主。Objective To compare ovarian function changes and the mechanisms of aging and apoptosis in mouse models of premature ovarian failure(POF)induced by different doses of cyclophosphamide(CTX),and to identify the optimal modeling method.Methods Thirty female C57BL/6 mice aged 6~8 weeks were randomly divided into six groups:the Control group,POF1 group 120 mg/kg,POF2 group 200 mg/kg,POF3 group 50 mg/kg×14 days,POF4 group 400 mg/kg,and POF5 group 25 mg/kg×14 days.The mice received intraperitoneal injections of cyclophosphamide(CTX),respectively.The ovarian function,as well as changes in senescence and apoptosis,were recorded and compared under different CTX doses and administration frequencies in the POF mouse models.Results Compared to the control group,all model groups exhibited disrupted estrous cycles,reduced sex hormone expression,increased ovarian fibrosis,and a decrease in follicle count(P<0.05).The expressions of anti-Müllerian hormone(AMH)and follicle-stimulating hormone receptor(FSHR)were significantly reduced(P<0.05),and the severity of ovarian damage was positively correlated with CTX dose(|r|>0.500,P<0.05).Additionally,all model groups showed increased cellular senescence and apoptosis.In the POF1,POF2,and POF5groups,the expressions of senescence-related molecules such as cyclin-dependent kinase inhibitor 2A(p16),cyclindependent kinase inhibitor 1A(p21),and senescence-associatedβ-galactosidase(β-gal)were significantly higher than those in the POF3 group(P<0.05).Conversely,in the POF3 group,apoptosis-related molecules such as Bcl-2-associated X protein(Bax),cysteine-aspartic acid protease 3(Caspase3),and phosphorylated H2A histone family member X(γ-H2AX)were significantly more highly expressed than in the POF2 and POF5 groups(P<0.05).Conclusions CTX at different doses can induce POF in mice,with the severity of ovarian damage increasing in a dose-dependent manner.Lower doses of CTX primarily cause ovarian damage through cellular senescence mechanisms,while higher doses primarily induce ovarian damage

关 键 词：卵巢早衰 动物模型 细胞衰老 细胞凋亡 

分 类 号：R711.75[医药卫生—妇产科学] R-332[医药卫生—临床医学]