{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T01:14:32Z","timestamp":1794014072242,"version":"4.8.0"},"reference-count":50,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Folic acid (FA) is widely used to support one\u2010carbon metabolism; however, at high doses, it can circulate predominantly as unmodified FA (UMFA), potentially leading to metabolic imbalances and adverse effects on reproductive performance. This study aimed to compare the effects of high doses (20X) of FA and 5\u2010methyltetrahydrofolate (5mTHF) on the developmental competence of mouse oocytes, both in\u00a0vitro and in\u00a0vivo, using standard dose FA as a control. For the in\u00a0vitro experiment, female mice were hormonally stimulated and the collected cumulus\u2010oocyte\u2010complexes (COCs) were matured in\u00a0vitro with the add\u2010on of variable concentrations of FA or 5mTHF, and the reproductive outcomes were recorded. In\u00a0vivo, 3\u2010week female mice received high\u2010dose FA or 5mTHF supplementation during the weaning period (5\u2009weeks), after which they were either mated with fertile males or hormonally stimulated for COCs collection. Results indicated that high FA concentrations impaired oocyte maturation, spindle assembly, fertilization, and blastocyst development, whereas similar high concentrations of 5mTHF did not induce such deterioration and even improved some outcomes. Post\u2010mating, high\u2010dose FA increased embryo reabsorption rates, while 5mTHF reduced them. Blood analyses showed comparable folate levels across groups, but high\u2010dose FA significantly raised formaldehyde levels\u2014a genotoxic metabolite\u2014whereas 5mTHF markedly decreased formaldehyde. In\u00a0vitro, 5mTHF supported better oocyte maturation compared to FA, and in\u00a0vivo, it provided reproductive benefits without inducing formaldehyde toxicity. These findings suggest 5mTHF as a safer, more effective folate form for reproductive health, emphasizing concerns over high\u2010dose FA's genotoxic potential and advocating for cautious clinical use.<\/jats:p>","DOI":"10.1096\/fj.202501768r","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T06:28:45Z","timestamp":1760336925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential Effects of Folic Acid and 5\u2010Methyltetrahydrofolate on Mice Oocytes and Embryo Development In\u00a0Vitro and In\u00a0Vivo: Implications for Reproductive Health"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-5201-7458","authenticated-orcid":false,"given":"Fatemeh","family":"Nasr\u2010Esfahani","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Science and Technology ACECR Institute of Higher Education  Isfahan 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