大鼠致畸试验中阳性对照环磷酰胺的给药方法研究

doi:10.3969/j.issn.1004-616x.2013.03.014

癌变·畸变·突变

大鼠致畸试验中阳性对照环磷酰胺的给药方法研究

杨润芳^1，2,郭海东³,夏祺悦^1，2,刘强强¹,徐策¹,卓衍蔷_¹,李宏霞^1，*

( 1. 四川大学华西医院国家成都中药安全性评价中心，四川成都 610041；2. 四川大学华西公共卫生学院，四川成都 610041；3. 公安部四川消防研究所，四川成都 610036 )

收稿日期:2012-10-22 修回日期:2013-02-25 出版日期:2013-05-30 发布日期:2013-05-30
通讯作者: 李宏霞，E-mail：hxl9998@sohu.com
作者简介:杨润芳(1987- )，女，山西人，硕士研究生，研究方向：药物毒理学。
基金资助:
国际科技合作项目(2009DFA31020)

Cyclophosphamide as a positive control in teratogenicity test of rats

YANG Run-fang^1，2，GUO Hai-dong³，XIA Qi-yue^1，2，LIU Qiang-qiang¹，XU Ce¹，ZHUO Yan-qiang¹，LI Hong-xia^1，*

(1. National Center for Safety Evaluation of Traditional Medicine, West China Hospital of Sichuan University, Chengdu 610041; 2. West China School of Public Health, Sichuan University, Chengdu 610041; 3. Sichuan Fire Research Institute of Ministry of Public Security, Chengdu 610036, Sichuan, China)

Received:2012-10-22 Revised:2013-02-25 Online:2013-05-30 Published:2013-05-30
Contact: LI Hong-xia，E-mail：hxl9998@sohu.com

摘要/Abstract

摘要：

目的：比较致畸敏感期环磷酰胺不同给药方案对孕鼠的致畸效应，确定一种最佳的给药方案以指导环磷酰胺作为大鼠致畸敏感期生殖毒性试验阳性对照的使用。方法：交配成功的SD大鼠随机分为3组，每组10只，分别为：环磷酰胺连续给药组 (A组)，于妊娠第6~15天 (即GD6～GD15)每天按4.8 mg/kg皮下注射给予环磷酰胺；环磷酰胺单次给药组 (B组)，于GD12一次性按12 mg/kg皮下注射给予环磷酰胺；对照组 (C组)，于GD6～GD15每天皮下注射给予大鼠相应体积的生理盐水。孕期称取母鼠体质量并观察一般状况，于GD20用CO2对孕鼠实施安乐死，解剖后称重并记录其生殖器官质量，检查胎仔外观、骨骼和内脏畸形情况。结果：两个环磷酰胺给药组一般状况观察均未见异常；B组子宫胎盘质量、胎盘质量、子宫质量低于对照组 (P<0.05)。外观检查，A组未出现显著的畸形种类；B组能引起明显的外观畸形，主要有脑膜膨出、小头、脑露、足内翻等。内脏检查，A组显著增加的畸形仅见侧脑室扩大或淤血；B组出现明显的内脏畸形，主要表现为第三脑室扩大或淤血、侧脑室扩大或淤血、心室心房异常等。骨骼检查，A组骨骼畸形种类较少，且与对照组比较差异无统计学意义；B组大部分骨骼畸形发生率比对照组高，主要表现在头部和胸腔，如基蝶骨异常、肋骨数目异常等。结论：在本试验条件下，大鼠于GD12按12 mg/kg经皮下注射给予环磷酰胺为较为理想的阳性对照给药方法，显示出更宽的畸形谱和更重的畸形程度，推荐在大鼠致畸敏感期生殖毒性试验中选用。

关键词: 环磷酰胺, 阳性对照, 大鼠, 发育毒性, 致畸作用

Abstract:

OBJECTIVE: Two procedures were chosen to study cyclophosphamide (CP) as a positive control in teratogenicity test of rats. One procedure was dosing CP 4.8 mg/kg from gestation day 6 (GD6) to GD15 continuously (group A). The other procedure was single dosing of CP 12 mg/kg on gestation day 12 (GD12) (group B). METHODS：The successfully mated SD rats were divided into three groups randomly，namely group A (dosing CP 4.8 mg/kg from GD6 to GD15 continuously)，group B (single dosing CP 12 mg/kg on GD12) and group C (the saline negative control group). The general condition of the treated rats was observed and the body weight was recorded every three days. Pregnant rats were euthanized by CO2 on GD20 for autopsy and reproductive organs were weighed. Fetal appearance， internal organs and skeletal malformations were checked and recorded. RESULTS：General conditions in group A and B were normal when compared with group C . Weights of uterus with placentas，placentas and uterus in group B were statistically lower than group C (P<0.05). Fetal appearance in group A showed no significant difference when compared with group C ，while in group B there were obvious deformities，including meningocele，microcephaly， brain exposed，club-foot，etc. Fetal internal organs examination in group A showed only the lateral cerebral ventricle enlarged or congested. However in group B internal organs malformations were found including the third and lateral cerebral ventricles enlarged or congested，and abnormal cardiac atrium or cardiac ventricle. Fetal skeletal examination showed little malformation in group A，with no significant difference when compared with group C. In group B，skeletal deformities incidence was higher in most bones than group C，mainly in the head and thorax，such as basisphenoid abnormalities，abnormal number of ribs，etc. CONCLUSION：In this experiment，dosing CP 12 mg/kg on GD12 induced more severe and more types of fetal malformation than dosing CP 4.8 mg/kg from GD6 to GD15 continuously. Therefore，dosing CP 12 mg/kg on GD12 was recommended as an effective positive control procedure in teratogenicity test of rats.

Key words: cyclophosphamide, positive control, rat, developmental toxicity, teratogenicity

杨润芳,郭海东,夏祺悦,刘强强,徐策,卓衍蔷,李宏霞. 大鼠致畸试验中阳性对照环磷酰胺的给药方法研究[J]. 癌变·畸变·突变, doi: 10.3969/j.issn.1004-616x.2013.03.014.

YANG Run-fang，GUO Hai-dong，XIA Qi-yue，LIU Qiang-qiang，XU Ce，ZHUO Yan-qiang，LI Hong-xia. Cyclophosphamide as a positive control in teratogenicity test of rats[J]. Carcinogenesis, Teratogenesis & Mutagenesis, doi: 10.3969/j.issn.1004-616x.2013.03.014.

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大鼠致畸试验中阳性对照环磷酰胺的给药方法研究

Cyclophosphamide as a positive control in teratogenicity test of rats

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