{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T01:35:52Z","timestamp":1772847352454,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2012,7,13]],"date-time":"2012-07-13T00:00:00Z","timestamp":1342137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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\u2010mutant 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\u2009mg kg<jats:sup>\u20131<\/jats:sup> 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\u2009mg kg<jats:sup>\u20131<\/jats:sup> b\/w, resulted in the highest incidence of NTDs (31.4%) compared with the other groups, and DHFR activities, 5\u2010MeTHF and 5\u2010FoTHF concentrations in embryonic tissues decreased significantly after MTX injection. Furthermore, we found three high\u2010confidence CNVs on chromosome X using aCGH, which was confirmed by RT\u2010PCR and MassARRAY. These results indicate that MTX could cause a folate\u2010associated 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 \u00a9 2012 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.2769","type":"journal-article","created":{"date-parts":[[2012,7,13]],"date-time":"2012-07-13T18:07:23Z","timestamp":1342202843000},"page":"915-923","source":"Crossref","is-referenced-by-count":22,"title":["Influence of the antifolate drug Methotrexate on the development of murine neural tube defects and genomic instability"],"prefix":"10.1002","volume":"33","author":[{"given":"Jie","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Shanxi Medical University  Taiyuan 030001 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Guan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Shanxi Medical University  Taiyuan 030001 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Xiang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences Peking Union Medical College  Beijing 100730 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Medical Sciences Peking Union Medical College  Beijing 100730 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiuwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Guan","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiu","family":"Xie","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Niu","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2012,7,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(91)90133-A"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.38.072902.092448"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrc.20100"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199911113412001"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20632"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1028-4559(08)60002-9"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1028-4559(08)60003-0"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2011.07.010"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741-4520.2008.00189.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9926(199606)53:6<345::AID-TERA5>3.0.CO;2-Z"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/132.8.2444S"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1027"},{"key":"e_1_2_6_14_1","first-page":"683","article-title":"Drug\u2010induced teratogenesis","volume":"87","author":"Fraser FC","year":"1962","journal-title":"Can. 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