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Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex‐Specific Placental Transcription Changes
Author(s) -
Luan Yan,
Leclerc Daniel,
CosínTomás Marta,
Malysheva Olga V.,
Wasek Brandi,
Bottiglieri Teodoro,
Caudill Marie A.,
Rozen Rima
Publication year - 2021
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.202100197
Subject(s) - methylenetetrahydrofolate reductase , endocrinology , medicine , choline , placenta , pregnancy , biology , methylation , fetus , biochemistry , gene , genetics , genotype
Scope Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. It is reported that diets containing five‐fold 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. Methods and Results 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‐MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S‐adenosylmethionine:S‐adenosylhomocysteine ratio) and glycerophosphocholine are decreased in placenta and embryonic liver. Folic acid supplemented diet results in sex‐specific 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. Conclusion 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.