CN114208776B - 一种雄性不育症小鼠模型的构建方法 - Google Patents
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Abstract
本发明涉及动物模型构建技术领域，具体涉及一种雄性不育症小鼠模型的构建方法。所述方法是将5周龄雄性小鼠经过如下处理：经饮水持续暴露氯化镉水溶液，并喂养高脂饲料；所述小鼠为SPF级C56BL/6小鼠，氯化镉水溶液的浓度为95‑105mg/L，高脂饲料为60％fat高脂饲料，整个处理维持2个生精周期。本发明的造模方法简单，模型中精子数量、精子活力和受孕率等指标稳定性好，可重复性强，为不育症的构建，提供了一种可靠的方法，构建得到的模型可用于探讨不育症的作用机制和分子靶标，筛选治疗不育症的药物。
Description
技术领域
本发明涉及动物模型构建技术领域，具体涉及一种雄性不育症小鼠模型的构建方法。
背景技术
育龄夫妇在未采取任何避孕措施的情况下正常进行性生活，一年甚至更长时间未怀孕或者生育，则可在临床上定义为不孕不育症。不育症会导致严重的心理和社会压力，并给患者和医疗保健系统带来巨大经济负担。已知，精液质量下降是导致男性不育的重要原因。自上世纪70年代以来，全球男性精液质量下降已超过52％，但其确切机制尚不明确。因此，男性不育已成为迫切需要解决的公共卫生问题，急需建立稳定的男性不育动物模型，探讨精液质量下降的确切机制，寻找干预措施。
目前，引起精液质量快速下降的主要因素是环境因素和生活方式。镉是环境中广泛存在的有毒重金属，工业生产中排放含镉废水废气、电子垃圾拆卸回收、农业生产中使用含镉化肥以及矿产开发等均可引起环境镉污染。流行病学研究表明，精液重金属镉浓度与精子质量呈现负相关。另外，随着生活水平的提高，过量摄入高脂肪类食物、久坐不动等生活方式导致超重和肥胖人数呈现大幅度增长趋势。肥胖也是引起精子质量下降的重要原因之一。Sermondade等对包括13077名男性在内的21项研究进行荟萃分析发现，体重指数(BMI)的增加与少精子症和无精子症的风险呈正相关。以上均提示，环境因素和生活方式是导致男性不育的重要原因。因此，探究不良环境因素和生活方式联合暴露对男性不育发生的影响及其机制，合理规避不良环境因素和生活方式暴露，对提高生育能力，指导优生优育具有重要的现实意义。
然而，现有的不育症动物模型均为单一因素处理，如给予环境内分泌干扰物双酚A处理，导致小鼠生殖细胞凋亡增加和精子数量降低；给予小鼠睾丸热应激处理，导致生殖细胞死亡、精子数量和活力降低；手术致隐睾症和精索静脉曲张症等。这些造模方法虽能模拟不育症发生的疾病表型但模型稳定性差，且未能正确反映人类复合暴露方式，在人类不育症发病机制方面存在较大的差异。因此，现有研究迫切需要建立稳定且与人类男性不育症高度相似的小鼠模型，筛选出致生殖毒性的新型化学品，探究其安全范围，进一步造福人类。
发明内容
针对上述技术问题，本发明的目的在于提供一种成功率高、有效可靠，可重复强、简单易行的雄性不育症小鼠模型的构建方法。
为实现上述目的，本发明采用如下技术方案：
一种雄性不育症小鼠模型的构建方法，是将5周龄雄性小鼠经过如下处理：
经饮水持续暴露氯化镉水溶液，并喂养高脂饲料。
进一步的，所述小鼠为SPF级C56BL/6小鼠。
更进一步的，所述氯化镉水溶液的浓度为95-105mg/L。
更进一步的，所述高脂饲料为60％fat高脂饲料。
更进一步的，整个处理维持2个生精周期。
本发明具有如下有益效果：
(1)本发明的造模方法简单，模型中精子数量、精子活力和受孕率等指标稳定性好，可重复性强，为不育症的构建，提供了一种可靠的方法。
(2)基于本发明构建的不育症模型，可用于模拟人类环境化学毒物和生活方式暴露方式，探讨不育症的作用机制和分子靶标，以及筛选不育症的治疗药物。
附图说明
图1为不同处理对受孕率的影响，数据表示为均数±标准误。aP＜0.05，与对照组比较；bP＜0.05，与镉组比较。
图2为不同处理组小鼠的精子质量评价，数据表示为均数±标准误。(A)精子计数图；(B)精子数量统计图；aP＜0.05，与对照组比较；bP＜0.05，与镉组比较；cP＜0.0S，与高脂组比较。
图3为不同处理组小鼠的睾丸发育评价。数据表示为均数±标准误。(A)睾丸HE染色；(B)不同期生精小管比例；(C)睾丸生殖细胞标记物mRNA水平；aP＜0.05，与对照组比较；bP＜0.05，与镉组比较；cP＜0.05，与高脂组比较。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明，但不应理解为本发明的限制。如未特殊说明，下述实施例中所用的技术手段为本领域技术人员所熟知的常规手段，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1：雄性不育症小鼠模型的构建
1.实验动物：
SPF级健康C56BL/6J小鼠够买于北京维通利华实验动物技术有限公司。本研究获安徽医科大学伦理委员会批准，并严格按照国际实验动物保护认证评估机构相关处理准则执行。实验动物饲养于SPF级环境内，温度22～25℃，湿度50％，12h昼夜交替。
2.实验方法：
40只5周龄雄鼠被随机分为4组，即对照组、镉(Cd)处理组、高脂(HFD)处理组和高脂加镉(HFD+Cd)联合处理组。Cd处理组小鼠经饮水暴露氯化镉水溶液(100mg/L)，HFD处理组小鼠喂养60％fat高脂饲料，HFD+Cd处理组小鼠经饮水暴露氯化镉水溶液(100mg/L)，并喂养60％fat高脂饲料，对照组全程饮用反渗透(RO)水和喂养低脂对照饲料。饲料购自南通特洛菲饲料科技有限公司。HFD和Cd暴露2个生精周期(70天)后与正常雌鼠合笼交配，然后麻醉处死雄鼠，取小鼠睾丸和精子。
3.检测指标与方法：
3.1受孕率计算
于晚上9:00将雄鼠与正常雌鼠按1∶1比例进行交配，次日早上7:00阴道涂片，确定受孕小鼠。连续三天，计算雌鼠受孕率。
3.2精子质量评价
取小鼠左侧附睾放入预热的培养基中，在37℃下剪碎附睾并孵育5分钟使精子充分游出。吸取精子悬液，在全自动精子分析仪(Hamilton Thorne IVOS II)中检测精子数量、精子活力和精子运动参数等。
3.3睾丸发育评价
取小鼠睾丸，部分制作石蜡切片，进行苏木精-伊红(HE)染色，观察小鼠睾丸生精小管间隙、生殖细胞排列，评价生精小管分期。部分提取总RNA，逆转录(RT)后，再行实时定量聚合酶链反应(PCR)检测睾丸各种生殖细胞标记物表达情况。
4.实验结果
4.1高脂和镉联合暴露降低受孕率
高脂和镉联合暴露对受孕率的影响如图1所示。与对照组相比，高脂组和高脂加镉组受孕率降低。与镉组相比，高脂加镉组受孕率进一步降低。实验结果表明，高脂和镉联合暴露稳定降低受孕率。
4.2高脂和镉联合暴露降低精子质量
高脂和镉联合暴露对精子质量的影响如图2和表1所示。与对照组相比，镉组、高脂组、高脂加镉组精子数量均降低。与镉组相比，高脂组和高脂加镉组受精子数量降低。与高脂组相比，高脂加镉组精子数量进一步降低。另外，与对照组相比，高脂加镉组精子活力和精子运动参数，如前进性活动精子百分比、平均移动速率、直线移动速率和曲线移动速率等均明显降低。实验结果表明，高脂和镉联合暴露稳定降低精子质量。
表1高脂和镉联合暴露对精子活力和精子运动参数的影响
数据表示为均数±标准误。*P＜0.05，**P＜0.01，与对照组相比。
4.3高脂和镉联合暴露损害睾丸发育
高脂和镉联合暴露对睾丸发育的影响如图3所示。与对照组相比，镉组、高脂组、高脂加镉组成熟期生精小管比例、精母细胞标记物(Smc3)、圆形精子标记物(Acrv1)和长型精子标记物(Lzumo3)均降低。与镉组相比，高脂加镉组成熟期生精小管比例、精母细胞标记物、圆形精子标记物和长型精子标记物进一步降低。实验结果表明，高脂和镉联合暴露稳定损害睾丸发育。
本发明方法通过给予5周龄雄鼠高脂和镉联合处理2个生精周期，实验组出现受孕率降低、精子质量下降和睾丸发育受损等不育症类似的典型特征，说明成功建立了男性不育症模型。本发明的造摸方法简单，模型中受孕率、精子数量、精子活力和睾丸发育等指标稳定性好，说明本发明造模方法稳定有效可靠，可重复性强。
实施例2：雄性不育症小鼠模型的潜在应用
1.将环境毒物和生活方式改变施用于实施例1的动物模型，观察候选的环境毒物和生活方式对不育症的各种指标的影响情况，评价具有潜在危害的环境毒物和生活方式。
2.将治疗不育症的候选药物施用于实施例1的动物模型，筛选能够治疗不育症的药物。
综上，本发明的造模方法通过给予5周龄雄鼠高脂和镉联合处理2个生精周期，实验组出现受孕率降低、精子质量下降和睾丸发育受损等不育症类似的典型特征，是建立不育症的有效方法，可用于模拟人类环境毒物和生活方式暴露方式，探讨不育症的作用机制和分子靶标，以及筛选不育症的治疗药物。
需要说明的是，本发明权利要求书中涉及数值范围时，应理解为每个数值范围的两个端点以及两个端点之间任何一个数值均可选用，为了防止赘述，本发明描述了优选的实施例。
尽管已描述了本发明的优选实施例，但本领域内的技术人员一旦得知了基本创造性概念，则可对这些实施例作出另外的变更和修改。所以，所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (5)
1.一种雄性不育症小鼠模型的构建方法，其特征在于，是将5周龄雄性小鼠经过如下处理：
经饮水持续暴露氯化镉水溶液，并喂养高脂饲料，所述小鼠模型精子质量降低，睾丸发育受损，且与正常雌鼠交配，雌鼠受孕率降低；所述精子质量包括：精子活力、前进性活动精子百分比、平均移动速率、直线移动速率、曲线移动速率和头部移动距离。
2.根据权利要求1所述的一种雄性不育症小鼠模型的构建方法，其特征在于所述小鼠为SPF级C56BL/6小鼠。
3.根据权利要求2所述的一种雄性不育症小鼠模型的构建方法，其特征在于所述氯化镉水溶液的浓度为95-105mg/L。
4.根据权利要求3所述的一种雄性不育症小鼠模型的构建方法，其特征在于所述高脂饲料为60％fat高脂饲料。
5.根据权利要求4所述的一种雄性不育症小鼠模型的构建方法，其特征在于整个处理维持2个生精周期。
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