Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability
Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability
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抗叶酸药物甲氨蝶呤对小鼠神经管缺陷发展和基因组不稳定性的影响
DOI：
10.1002/jat.2769
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发表时间：
2013-09
影响因子：
3.3
通讯作者：
Bo Niu
中科院分区：
文献类型：
--
作者：
Ting Zhang;Tao Guan;Jianhua Wang;Qian Xiang;Mingsheng Wang;Xiuwei Wang;Zhen Guan;Qiu Xie;Bo Niu
叶酸代谢受损被认为是神经管缺陷 (NTD) 的危险因素。然而，叶酸缺乏与 NTD 风险之间的关系仍不清楚，因为实验诱导的膳食叶酸缺乏不足以在非突变小鼠中引起 NTD。甲氨蝶呤 (MTX) 是一种特异性叶酸拮抗剂，可竞争性抑制二氢叶酸还原酶 (DHFR) 活性。本研究的目的是建立叶酸代谢障碍小鼠模型，并研究 NTD 的发生及其机制。怀孕小鼠在妊娠第 7.5 天腹膜内注射不同剂量的 MTX [0、0.5、1.0、3.0、4.5 和 6.0mg kg–1 体重 (b/w)]，并在妊娠第 11.5 天处死。检测胚胎组织中的 DHFR 活性，并使用 LC/MS/MS 分析叶酸浓度。使用阵列比较基因组杂交（aCGH）检测神经管组织中的拷贝数变异（CNV）。与其他组相比，MTX 4.5mg kg–1 b/w 的剂量导致 NTD 发生率最高（31.4%），注射 MTX 后胚胎组织中 DHFR 活性、5-MeTHF 和 5-FoTHF 浓度显着降低。此外，我们使用aCGH在X染色体上发现了三个高置信度的CNV，并通过RT-PCR和MassARRAY证实。这些结果表明，MTX 可能会导致与叶酸相关的代谢障碍，这与小鼠膳食叶酸缺乏的情况相似。神经管组织中 CNV 的存在与 NTD 的发生有关。版权所有 © 2012 约翰·威利父子有限公司
Impaired folate metabolism is considered a risk factor for neural tube defects (NTDs). However, the relationship between folate deficiency and the risk of NTDs remains unclear, because experimentally induced dietary folate deficiency is insufficient to cause NTDs in non‐mutant mice. Methotrexate (MTX) is a specific folate antagonist that competitively inhibits dihydrofolate reductase (DHFR) activity. The objective of this study was to develop a folate dysmetabolism murine model, and study the development of NTDs and its mechanism. Pregnant mice were injected with different doses of MTX [0, 0.5, 1.0, 3.0, 4.5 and 6.0 mg kg–1 body weight (b/w) intraperitoneally (i.p.)] on gestational day 7.5 and sacrificed on gestational day 11.5. DHFR activity in embryonic tissues was detected, and folate concentrations were analyzed using LC/MS/MS. Copy number variations (CNVs) in neural tube tissues were detected using array comparative genomic hybridization (aCGH). A dose of MTX 4.5 mg kg–1 b/w, resulted in the highest incidence of NTDs (31.4%) compared with the other groups, and DHFR activities, 5‐MeTHF and 5‐FoTHF concentrations in embryonic tissues decreased significantly after MTX injection. Furthermore, we found three high‐confidence CNVs on chromosome X using aCGH, which was confirmed by RT‐PCR and MassARRAY. These results indicate that MTX could cause a folate‐associated dysmetabolism, which is similar to that of dietary folate deficiency in mice. The presence of CNVs in neural tube tissues was associated with the development of NTDs. Copyright © 2012 John Wiley & Sons, Ltd.
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DOI：
10.1002/bdra.20271
发表时间：
2006-06
期刊：
Birth defects research. Part A, Clinical and molecular teratology
影响因子：
--
作者：
Le Zhang;A. Ren;Zhiwen Li;Ling Hao;Yi-hua Tian;Zhu Li
通讯作者：
Le Zhang;A. Ren;Zhiwen Li;Ling Hao;Yi-hua Tian;Zhu Li
DOI：
10.1097/00006254-200004000-00006
发表时间：
2000-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
R. Berry;Zhu Li;J. Erickson;Song Li;C. Moore;Hong Wang;J. Mulinare;P. Zhao;Lee-Yang C. Wong-Lee-Yang
通讯作者：
R. Berry;Zhu Li;J. Erickson;Song Li;C. Moore;Hong Wang;J. Mulinare;P. Zhao;Lee-Yang C. Wong-Lee-Yang
影响因子：
2.7
作者：
Xu Wang;M. Fenech
通讯作者：
Xu Wang;M. Fenech
影响因子：
3.7
作者：
Sun, Shuna;Gui, Yonghao;Song, Houyan
通讯作者：
Song, Houyan
影响因子：
7.7
作者：
Wentzel, P;Gäreskog, M;Eriksson, UJ
通讯作者：
Eriksson, UJ