{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T17:46:48Z","timestamp":1771350408710,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,8,13]],"date-time":"2014-08-13T00:00:00Z","timestamp":1407888000000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 HD067244"],"award-info":[{"award-number":["RO1 HD067244"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37 HL087062"],"award-info":[{"award-number":["R37 HL087062"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM073546"],"award-info":[{"award-number":["T32 GM073546"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Neural tube closure defects (NTDs) are among the most common congenital malformation in human, typically presenting in liveborns as spina bifida. At least 240 gene mutations in mouse are known to increase the risk of NTD. There is a growing appreciation that environmental factors significantly contribute to NTD expression, and that NTDs likely arise from complex gene\u2010environment interactions. Because maternal folic acid supplementation reduces human NTD risk in some populations by 60 to 70%, it is likely that NTD predisposition is often associated with a defect in folate\u2010dependent one\u2010carbon metabolism. A comprehensive, untargeted metabolic survey of NTD\u2010associated changes in embryo metabolism would provide a valuable test of this assumption. We sought to establish a metabolic profiling platform that is capable of broadly assessing metabolic aberrations associated with NTD\u2010promoting gene mutations in early\u2010stage mouse embryos.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A liquid chromatography\/mass spectrometry\u2010based untargeted metabolite profiling platform was used to broadly identify significant differences in small molecule levels (50\u20131000 Da) in NTD\u2010affected embryonic day (E) 9.5 mouse embryos (<jats:italic>Lrp6<jats:sup>\u2212<\/jats:sup><jats:sup>\/<\/jats:sup><jats:sup>\u2212<\/jats:sup><\/jats:italic>) versus unaffected (<jats:italic>Lrp6<\/jats:italic><jats:sup>+\/+<\/jats:sup>) control embryos.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Results provide proof\u2010of\u2010principal feasibility for the broad survey of the metabolome of individual E9.5 mouse embryos and identification of metabolic changes associated with NTDs and gene mutations. Levels of 30 different metabolites were altered in association with Lrp6 gene deletion. Some metabolites link to folate\u2010dependent one\u2010carbon transfer reactions, as anticipated, while others await structure elucidation and pathway integration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>Whole\u2010embryo metabolomics<\/jats:italic>offers the potential to identify metabolic changes in genetically determined NTD\u2010prone embryos. Birth Defects Research (Part A) 100:623\u2013632, 2014. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23272","type":"journal-article","created":{"date-parts":[[2014,8,13]],"date-time":"2014-08-13T14:08:29Z","timestamp":1407938909000},"page":"623-632","source":"Crossref","is-referenced-by-count":15,"title":["Untargeted metabolite profiling of murine embryos to reveal metabolic perturbations associated with neural tube closure defects"],"prefix":"10.1002","volume":"100","author":[{"given":"Alex","family":"Hansler","sequence":"first","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College New York New York"},{"name":"Program in Pharmacology Weill Cornell Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason D.","family":"Gray","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Elizabeth","family":"Ross","sequence":"additional","affiliation":[{"name":"Feil Family Brain and Mind Research Institute, Weill Cornell Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard H.","family":"Finnell","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences Dell Pediatric Research Institute, The University of Texas at Austin Austin Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven S.","family":"Gross","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Weill Cornell Medical College New York New York"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,8,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005025"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.5.12.1916088"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2003.11.016"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-130708"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1986"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501963102"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/8.12.2199"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0037149"},{"key":"e_1_2_6_10_1","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1016\/S0022-3565(25)39582-0","article-title":"Methionine synthase inactivation by nitrous oxide during methionine loading of normal human fibroblasts. 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