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Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability
Author(s) -
Zhao Jie,
Guan Tao,
Wang Jianhua,
Xiang Qian,
Wang Mingsheng,
Wang Xiuwei,
Guan Zhen,
Xie Qiu,
Niu Bo,
Zhang Ting
Publication year - 2013
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.2769
Subject(s) - neural tube , dihydrofolate reductase , methotrexate , folate receptor , antifolate , methylenetetrahydrofolate reductase , biology , pharmacology , endocrinology , medicine , embryo , biochemistry , genetics , immunology , antimetabolite , cancer , gene , cancer cell , genotype
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.