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It is reported that diets containing five\u2010fold higher FA than recommended for mice (5xFASD) during pregnancy resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline\/methyl metabolism, with neurobehavioral abnormalities in newborns. The goal is to determine whether these changes have their origins in the placenta during embryonic development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Female mice are fed control diet or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo\u2010MTHFR deficiency in maternal liver and altered choline\/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S\u2010adenosylmethionine:S\u2010adenosylhomocysteine ratio) and glycerophosphocholine are decreased in placenta and embryonic liver. Folic acid supplemented diet results in sex\u2010specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202100197","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T17:59:52Z","timestamp":1621447192000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex\u2010Specific Placental Transcription Changes"],"prefix":"10.1002","volume":"65","author":[{"given":"Yan","family":"Luan","sequence":"first","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Health Center (MUHC) McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Leclerc","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Health Center (MUHC) McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Cos\u00edn\u2010Tom\u00e1s","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Health Center (MUHC) McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga V.","family":"Malysheva","sequence":"additional","affiliation":[{"name":"Division of Nutritional Sciences and Genomics Cornell University  Ithaca NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandi","family":"Wasek","sequence":"additional","affiliation":[{"name":"Center of Metabolomics, Institute of Metabolic Disease Baylor Scott &amp; White Research Institute  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[{"name":"Center of Metabolomics, Institute of Metabolic Disease Baylor Scott &amp; White Research Institute  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie A.","family":"Caudill","sequence":"additional","affiliation":[{"name":"Division of Nutritional Sciences and Genomics Cornell University  Ithaca NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3516-6329","authenticated-orcid":false,"given":"Rima","family":"Rozen","sequence":"additional","affiliation":[{"name":"Departments of Human Genetics and Pediatrics McGill University Health Center (MUHC) McGill University  Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(91)90133-A"},{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1542\/peds.98.5.911","volume":"98","author":"Botto L. 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