5- 氟尿嘧啶对神经管畸形胎鼠脑组织基因表达的影响

doi:10.3969/j.issn.2095-5340.2020.03.005

发育医学电子杂志

2020, Vol. 8

Issue (3): 213-219 DOI: 10.3969/j.issn.2095-5340.2020.03.005

结构畸形论著

5- 氟尿嘧啶对神经管畸形胎鼠脑组织基因表达的影响

王秀伟　官臻　朱智强　牛勃　王建华

首都儿科研究所　儿童发育营养组学北京市重点实验室，北京　100020

Effect of 5-fluorouracil on gene expression in embryonic brain tissues of mice with neural tube defects

Wang Xiuwei, Guan Zhen, Zhu Zhiqiang, et al

Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing 100020, China

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摘要

【摘要】 目的　利用 5- 氟尿嘧啶（5-fluorouracil，5-FU）诱导 C57BL/6J 小鼠神经管畸形（neural tube

defects，NTDs），观察 5-FU 对 NTDs 胎鼠脑组织基因表达的影响。方法　采用无特定病原体（specifific

pathogen free，SPF）级 C57BL/6J 小鼠，孕鼠随机分为实验组和对照组。在孕 7.5 d 时，实验组孕鼠腹腔注射 12.5 mg/kg 的 5-FU（叶酸相关代谢通路中关键酶胸苷酸合成酶抑制剂）；对照组孕鼠腹腔注射等体积的生理盐水。孕 13.5 d 时通过体视显微镜及 HE 染色观察胎鼠畸形及神经管发育情况。在此基础上利用表达谱芯片分析 NTDs 胎鼠脑组织中基因表达的变化，并利用实时荧光定量 PCR 进行验证。统计学方法采用 t 检验。结果　实验组小鼠 NTDs 的发生率为 42.3%（22/52），主要为露脑畸形；对照组无一例 NTDs。HE 染色可见 NTDs 胎鼠的端脑和后脑结构紊乱。表达谱芯片筛选出差异表达基因 137 个，其中表达上调的基因 40 个，表达下调的基因 97 个，这些基因主要参与了多器官发育、细胞增殖及分化等生物过程以及与脑部发育相关的重要通路。选择表达差异明显且与胚胎神经发育相关的基因 Avp、Hes3 和 Wnt1 进行实时荧光定量 PCR 验证，结果发现所验证的基因表达情况与表达谱芯片的结果一致。　结论 5-FU 可能通过影响胚胎神经发育过程中与神经发育相关基因 Avp、Hes3 及 Wnt1 等的表达，进而导致 NTDs 的发生。

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关键词: 神经管畸形')" href="#">

神经管畸形胚胎 5- 氟尿嘧啶小鼠基因芯片

Abstract:

【Abstract】 Objective To investigate the gene expression alteration in the brain tissue of neural tube defects (NTDs) fetal mice of C57BL/6J induced by 5-fluorouracil (5-FU). Methods Specifific pathogen free (SPF) C57BL/6J pregnant mice were randomly divided into the experimental group and the control group. 5-FU (12.5 mg/kg), thymidine synthase inhibitor, was injected intraperitoneally into pregnant C57BL/6J mice in the experimental group on gestational day 7.5. The pregnant mice in the control group were intraperitoneally injected with equal volume of normal saline. The malformation and neural tube closure were carefully observed by stereomicroscope and hematoxylin-eosin (HE) staining on gestational day 13.5. The expression of different genes was studied by microarray and verifified by real-time quantitative polymerase chain reaction (RT-qPCR). The statistics analysis was performed with t test. Results The incidence of NTDs was 42.31% (22/52), especially exencephaly in the experimental group. There were no NTDs in the control group. The structure of telencephalon and hindbrain were abnormal in NTD mice by HE staining. The 137 genes were signifificantly difference in NTD mice compared with the control group, of which 40 genes were up-regulated and 97 genes were down-regulated. These genes were mainly involved in the biological

processes of multicellular organismal development, cell proliferation, differentiation, and the important

pathways related to brain development. Avp, Hes3 and Wnt1 genes, which were neural development related

genes, were chosen and validated by RT-qPCR to show the signifificantly abnormal expressions in NTD brain

tissues. Conclusion 5-FU might affect the expressions of the Avp, Hes3 and Wnt1 genes related to neural

development during the process of embryonic brain development, and then lead to the occurrence of NTDs.

Key words: Neural tube defects')" href="#">

Neural tube defects Embryo 5-fluorouracil Mice Microarray

收稿日期: 2019-10-22 出版日期: 2020-07-30 发布日期: 2020-07-28 期的出版日期: 2020-07-30

基金资助:

国家自然科学基金（81600984、81571443、81700777）；北京市自然科学基金（7172038）；首都儿科研究所所级基金（FX-2018-05/04）

通讯作者: 王建华https://www.bch.com.cn/Html/Doctors/Main/Index_602.html E-mail: fywjh@163.com

引用本文:

王秀伟　官臻　朱智强　牛勃　王建华.

5- 氟尿嘧啶对神经管畸形胎鼠脑组织基因表达的影响

[J]. 发育医学电子杂志, 2020, 8(3): 213-219.
Wang Xiuwei, Guan Zhen, Zhu Zhiqiang, et al.

Effect of 5-fluorouracil on gene expression in embryonic brain tissues of mice with neural tube defects

. Journal of Developmental Medicine(Electronic Version), 2020, 8(3): 213-219.

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http://www.fyyxzz.com/CN/10.3969/j.issn.2095-5340.2020.03.005 或 http://www.fyyxzz.com/CN/Y2020/V8/I3/213

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