{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T23:39:30Z","timestamp":1774913970110,"version":"3.50.1"},"reference-count":38,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2013,7,9]],"date-time":"2013-07-09T00:00:00Z","timestamp":1373328000000},"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":[[2014,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Apoptosis and proliferation play important roles in embryonic development and are required for neural tube closure. The antifolate drug methotrexate (MTX) induces folate dysmetabolism by inhibition of dihydrofolate reductase and causes abnormal apoptosis and proliferation. In this study, we established an animal model of neural tube defects (NTDs) using MTX to investigate the role of apoptosis and proliferation in NTDs caused by folate deficiency. Differential gene expressions were studied by microarray and reverse transcription\u2013polymerase chain reaction in the NTD animal model. Results showed that 30.8% of NTDs were caused by using MTX in treatment regimens. Microarray indicated that 166 genes were significantly different between the control and NTD mice, including four apoptosis\u2010related genes (<jats:italic>Endog<\/jats:italic>, <jats:italic>Trp53<\/jats:italic>, <jats:italic>Casp3<\/jats:italic>, <jats:italic>Bax<\/jats:italic>) and three proliferation\u2010related genes (<jats:italic>Ptch1<\/jats:italic>, <jats:italic>Pla2g4a<\/jats:italic>, <jats:italic>Foxg1<\/jats:italic>). Levels of <jats:italic>Endog<\/jats:italic>, <jats:italic>Trp53<\/jats:italic>, <jats:italic>Casp3<\/jats:italic>, <jats:italic>Bax<\/jats:italic> (fold change\u2009&gt;\u20091.5) were upregulated but <jats:italic>Ptch1<\/jats:italic>, <jats:italic>Pla2g4a<\/jats:italic>, <jats:italic>Foxg1<\/jats:italic> (fold change\u2009&lt;\u20090.67) were downregulated (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). These results were confirmed by reverse transcription\u2013polymerase chain reaction. TUNEL, immunohistochemical assays and Western blot were further used to detect apoptosis and proliferation in the NTD animal model. It was found that apoptosis in neuroepithelial cells was increased as determined by TUNEL (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). Expressions of caspase\u20103 were significantly enhanced (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) but expressions of phosphohistone H3 were greatly decreased (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05). These results concluded that MTX caused a folate and folate\u2010associated dysmetabolism, and further induced abnormal apoptosis and proliferation, which may play a critical role in the occurrence of NTDs caused by folate deficiency. Copyright \u00a9 2013 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/jat.2901","type":"journal-article","created":{"date-parts":[[2013,7,9]],"date-time":"2013-07-09T03:34:56Z","timestamp":1373340896000},"page":"862-869","source":"Crossref","is-referenced-by-count":24,"title":["Role of methotrexate exposure in apoptosis and proliferation during early neurulation"],"prefix":"10.1002","volume":"34","author":[{"given":"Xiuwei","family":"Wang","sequence":"first","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics  Beijing 100020 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Municipal Key Laboratory of Child Development and Nutriomics Capital Institute of Pediatrics  Beijing 100020 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