ArticlePloS one2014
Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
48 citing papers in PubMed, 2 syntheses or guidelines pooled it, 93 citations in OpenAlex.
- Unmetabolized Folic Acid: Biology, Epidemiology, and Clinical Consequences: A Systematic Review.Nutrients · 2026Pooled it
- Precision medicine in women with epilepsy: The challenge, systematic review, and future direction.Epilepsy & behavior : E&B · 2021Pooled it
- Human α-galactosidase A is stimulated by folic acid supplementation - possible implications in Fabry disease management.PloS one · 2026Article
- Folate in autism neurodevelopment.Frontiers in nutrition · 2026Review
- Vitamins, Vascular Health and Disease.Nutrients · 2025Review
- Effect of folic acid diet on the behavior of female mice and ultrasonic vocalization of their F1 offspring.IBRO neuroscience reports · 2025Article
- Article
- Fetal programming and lactation: modulating gene expression in response to undernutrition during intrauterine life.Pediatric research · 2024Article
- Risk of Excess Maternal Folic Acid Supplementation in Offspring.Nutrients · 2024Review
- Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review.Nutrients · 2023Review
- Prenatal folic acid supplement/dietary folate and cognitive development in 4-year-old offspring from the Japan Environment and Children's Study.Scientific reports · 2023Article
- Maternal methyl donor supplementation regulates the effects of cafeteria diet on behavioral changes and nutritional status in male offspring.Food & nutrition research · 2023Article
- The impact of early-life environment on absence epilepsy and neuropsychiatric comorbidities.IBRO neuroscience reports · 2022Review
- Folic acid supplementation during pregnancy alters behavior in male rat offspring: nitrative stress and neuroinflammatory implications.Molecular neurobiology · 2022Article
- Perinatal diet and offspring anxiety: A scoping review.Translational neuroscience · 2022Article
- Article
- Article
- Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease.Frontiers in nutrition · 2021Article
- Article
- A prospective birth cohort study on cord blood folate subtypes and risk of autism spectrum disorder.The American journal of clinical nutrition · 2020Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundStudies have indicated that altered maternal micronutrients and vitamins influence the development of newborns and altered nutrient exposure throughout the lifetime may have potential health effects and increased susceptibility to chronic diseases. In recent years, folic acid (FA) exposure has significantly increased as a result of mandatory FA fortification and supplementation during pregnancy. Since FA modulates DNA methylation and affects gene expression, we investigated whether the amount of FA ingested during gestation alters gene expression in the newborn cerebral hemisphere, and if the increased exposure to FA during gestation and throughout the lifetime alters behavior in C57BL/6J mice.
methodsDams were fed FA either at 0.4 mg or 4 mg/kg diet throughout the pregnancy and the resulting pups were maintained on the diet throughout experimentation. Newborn pups brain cerebral hemispheres were used for microarray analysis. To confirm alteration of several genes, quantitative RT-PCR (qRT-PCR) and Western blot analyses were performed. In addition, various behavior assessments were conducted on neonatal and adult offspring.
resultsResults from microarray analysis suggest that the higher dose of FA supplementation during gestation alters the expression of a number of genes in the newborns' cerebral hemispheres, including many involved in development. QRT-PCR confirmed alterations of nine genes including down-regulation of Cpn2, Htr4, Zfp353, Vgll2 and up-regulation of Xist, Nkx6-3, Leprel1, Nfix, Slc17a7. The alterations in the expression of Slc17a7 and Vgll2 were confirmed at the protein level. Pups exposed to the higher dose of FA exhibited increased ultrasonic vocalizations, greater anxiety-like behavior and hyperactivity. These findings suggest that although FA plays a significant role in mammalian cellular machinery, there may be a loss of benefit from higher amounts of FA. Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.
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