Impact of in Utero Folate Exposure on Dna Methylation and Its Potential Relevance for Later‐Life Health – Evidence from Mouse Models Translated to Human Cohorts

Kok, Dieuwertje E, Rebecca C, Richmond, Adriaens, Michiel, Evelo, Chris T., Ford, Dianne, Mathers, John C, Robinson, Natassia and Mckay, Jill (2022) Impact of in Utero Folate Exposure on Dna Methylation and Its Potential Relevance for Later‐Life Health – Evidence from Mouse Models Translated to Human Cohorts. Molecular Nutrition & Food Research, 66 (3). p. 2100789. ISSN 1613-4125

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Abstract

Scope: Persistent DNA methylation changes may mediate the effects of early-life exposures on later-life health. However, the human lifespan is challenging for prospective studies, therefore data from longitudinal studies are limited. Projecting data from mouse models of early-life exposure to existing human studies offers a potential tool to address this challenge.
Methods and Results: C57BL/6J mice were fed low or normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change;p<0.05). Processes/pathways potentially influenced by global changes, and function of these 8 genes, suggest neurocognitive effects. Human observational and randomized controlled trial data were interrogated for translational findings. Methylation at birth was inversely associated with maternal plasma folate in 6 of the genes (-1.15% to-0.16%/nmol/l;p<0.05), whilst maternal folic acid supplementation was associated with differential methylation of 4 of these genes in adulthood. Three CpGs were persistently hypermethylated with lower maternal folate (p = 0.04).
Conclusion: Some persistent folate-induced methylation changes observed in mice were mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

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