Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex-specific Placental Transcription Changes.

SCOPE Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. We reported that diets containing 5-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. Our goal was to determine whether these changes had their origins in the placenta during embryonic development. METHODS AND RESULTS Female mice were fed control diet (CD) 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 were decreased in placenta and embryonic liver. FASD resulted 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. This article is protected by copyright. All rights reserved.