Establishment Methods and Application Evaluation of Animal Models in Reproductive Toxicology Research

doi:10.12300/j.issn.1674-5817.2024.028

Abstract

Abstract:

Reproductive toxicology is a discipline that uses toxicological methods to study the mechanisms by which foreign substances interfere with the generation of eggs or sperm and their detrimental effects on offspring. Research includes evaluating the damaging effects of test substances on reproductive function of parents and the toxicity evaluation of offspring embryos. People are exposed to a wide range of drugs, chemicals and environmental pollutants on a daily basis, and determining whether these substances have reproductive toxicity is crucial for the health of future generations. Reproductive toxicology research is therefore critical. Given the specificity and importance of reproductive toxicity evaluation, corresponding institutions both domestically and internationally have issued guidelines, national standards, or industry standards, all of which involve animal experiments. In the study of reproductive system diseases, numerous animal models have been developed to investigate key reproductive organs, such as testicles and ovaries. Each model involves the selection of animals, the establishment of methods, and the quantification of evaluation indicators, and all have advantages and limitations. The choice of model should be based on experimental needs and the characteristics of the model. This paper summarizes commonly used animal models for reproductive and development toxicity evaluation in reproductive toxicology research, including rat models for fertility and early embryonic development toxicity, rat models for embryo-fetal development toxicity, rabbit models for embryo-fetal development toxicity evaluation, minipig models for embryo-fetal development toxicity, rat models for perinatal toxicity, zebrafish models for embryonic development toxicity, and models for evaluating ovarian toxicity induced by chemical drugs, radiotherapy, autoimmunity, and ovariectomy, as well as models for evaluating testicular toxicity caused by chemical drugs and environmental factors. The methods for establishing these models, their application scope, and characteristics are reviewed in order to provide references for relevant research applications.

Key words: Reproductive toxicology, Development toxicity, Perinatal toxicity, Testicular toxicity, Ovarian toxicity, Animal models

CLC Number:

R994

HUANG Dongyan,WU Jianhui. Establishment Methods and Application Evaluation of Animal Models in Reproductive Toxicology Research[J]. Laboratory Animal and Comparative Medicine, 2024, 44(5): 550-559. DOI: 10.12300/j.issn.1674-5817.2024.028.

Figures/Tables 3

References 42

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模型动物 Modeling animals	优点 Advantages	缺点 Disadvantages
大鼠 Rats	生物学资料全面；妊娠期短，生育力强；自发畸形率低；价格低廉，易获得	对性激素敏感，不适用于多巴胺受体激动剂和非固醇类抗炎药物的研究；对外源性蛋白的应用受限；药理活性有限或无活性
兔 Rabbits	同大鼠；且生殖道与人类最相似	对某些抗生素和消化道紊乱有易感性，其临床症状难以解释
小型猪 Minipigs	性成熟时间较其他非啮齿类动物短；器官发生期短（妊娠第11～35天）；与非人灵长类动物相比，多产，精子学资料与人类相似	胎盘缺乏转移大分子能力；妊娠期长（114 d）；受试物用量大，成本高；尚无用于研究的商业试剂盒
斑马鱼 Zebrafish	生殖周期短；每次产卵数量多；胚胎透明易观察，胎仔发育迅速；实验成本低	生殖系统基础资料相对缺乏；体外受精，与人类繁殖方式差异大

模型动物 Modeling animals	优点 Advantages	缺点 Disadvantages
大鼠 Rats	生物学资料全面；妊娠期短，生育力强；自发畸形率低；价格低廉，易获得	对性激素敏感，不适用于多巴胺受体激动剂和非固醇类抗炎药物的研究；对外源性蛋白的应用受限；药理活性有限或无活性
兔 Rabbits	同大鼠；且生殖道与人类最相似	对某些抗生素和消化道紊乱有易感性，其临床症状难以解释
小型猪 Minipigs	性成熟时间较其他非啮齿类动物短；器官发生期短（妊娠第11～35天）；与非人灵长类动物相比，多产，精子学资料与人类相似	胎盘缺乏转移大分子能力；妊娠期长（114 d）；受试物用量大，成本高；尚无用于研究的商业试剂盒
斑马鱼 Zebrafish	生殖周期短；每次产卵数量多；胚胎透明易观察，胎仔发育迅速；实验成本低	生殖系统基础资料相对缺乏；体外受精，与人类繁殖方式差异大

诱导药物 Inducing drugs	所用动物 Animals	给药方式 Administration	给药剂量和周期 Dose and time	评价指标 Evaluation indicators
环磷酰胺 Cyclophosphamide	家兔	腹腔注射	50 mg/kg连续2 d	血清FSH、E2 和AMH水平，卵巢组织病理学表现
	2～3月龄大鼠	腹腔注射	20 mg/kg，连续20 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	6～8周龄C57BL/6小鼠	腹腔注射	50 mg/kg，连续14 d；100 mg/kg，连续10 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
顺铂 Cisplatin	Wistar大鼠	腹腔注射	4 mg/kg, 第一次注射后间隔一周再注射	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	SD 大鼠	腹腔注射	6 mg/kg，第一次注射后间隔一周再注射
	C57BL/6小鼠	腹腔注射	50 mg/kg，连续7 d
雷公藤多苷片 Tripterygium glycosides tablet	Wistar大鼠	灌胃	50 mg/kg，连续14 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	7～8周龄SD鼠		400 μg/kg，连续60 d
	8周龄SD大鼠		50 mg/kg，连续14 d
	12周龄SD大鼠		40 mg/kg，连续70 d

诱导药物 Inducing drugs	所用动物 Animals	给药方式 Administration	给药剂量和周期 Dose and time	评价指标 Evaluation indicators
环磷酰胺 Cyclophosphamide	家兔	腹腔注射	50 mg/kg连续2 d	血清FSH、E2 和AMH水平，卵巢组织病理学表现
	2～3月龄大鼠	腹腔注射	20 mg/kg，连续20 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	6～8周龄C57BL/6小鼠	腹腔注射	50 mg/kg，连续14 d；100 mg/kg，连续10 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
顺铂 Cisplatin	Wistar大鼠	腹腔注射	4 mg/kg, 第一次注射后间隔一周再注射	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	SD 大鼠	腹腔注射	6 mg/kg，第一次注射后间隔一周再注射
	C57BL/6小鼠	腹腔注射	50 mg/kg，连续7 d
雷公藤多苷片 Tripterygium glycosides tablet	Wistar大鼠	灌胃	50 mg/kg，连续14 d	动情周期，血清FSH 、E2 和AMH水平，卵巢组织病理学表现
	7～8周龄SD鼠		400 μg/kg，连续60 d
	8周龄SD大鼠		50 mg/kg，连续14 d
	12周龄SD大鼠		40 mg/kg，连续70 d

建模方式 Modeling methods	优点 Advantages	缺点 Disadvantages
化学药物诱导 Chemical drugs induction	造模方法简单易行，周期短，成本低，模型稳定，应用最广	卵巢功能有自然恢复的可能性，不适合进行长期的探索性研究
放射疗法诱导 Radiotherapy induction	成功率高，可重复性强，周期短，能模拟临床放疗损伤导致的卵巢早衰	不易操作，对实验者的健康会产生潜在危害；在干预过程中对其他器官也会产生损伤，影响实验结果
自身免疫 Autoimmunity	模拟程度好，适用于免疫学相关的卵巢早衰生物医学研究	造模方法复杂，成功率低，周期长
卵巢切除 Ovariectomy	模拟程度好，对动物其他组织的损伤小	永久性的卵巢功能丢失，无法应用于卵巢早衰临床治疗研究
基因敲除 Gene knockout	能明确某一特定基因对卵巢早衰的作用	成本高，对实验技术要求高，存在外源性基因表达不稳定可能
超促排卵 Superovulation	有效模拟自然衰老卵巢特征，适合卵巢衰老绝经领域研究	应用相对较少，缺少背景资料