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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

Lookup NU author(s): Professor John Mathers



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbHScope: Persistent DNA methylation changes may mediate effects of early-life exposures on later-life health. Human lifespan is challenging for prospective studies, therefore data from longitudinal studies are limited. Projecting data from mouse models of early-life exposure to human studies offers a tool to address this challenge. Methods and Results: C57BL/6J mice were fed low/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 eight genes, suggest neurocognitive effects. Human observational and randomized controlled trial data were interrogated for translation. Methylation at birth was inversely associated with maternal plasma folate in six genes (−1.15% to −0.16% per nmol L−1; p < 0.05), while maternal folic acid supplementation was associated with differential methylation of four genes in adulthood. Three CpGs were persistently hypermethylated with lower maternal folate (p = 0.04). Conclusion: Some persistent folate-induced methylation changes in mice are mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

Publication metadata

Author(s): Kok DE, Richmond RC, Adriaens M, Evelo CT, Ford D, Mathers JC, Robinson N, McKay JA

Publication type: Article

Publication status: Published

Journal: Molecular Nutrition and Food Research

Year: 2022

Volume: 66

Issue: 3

Print publication date: 02/02/2022

Online publication date: 30/11/2021

Acceptance date: 30/11/2021

Date deposited: 13/01/2022

ISSN (print): 1613-4125

ISSN (electronic): 1613-4133

Publisher: John Wiley and Sons Inc


DOI: 10.1002/mnfr.202100789


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Funder referenceFunder name
Biotechnology and Biological Sciences Research Council. Grant Number: BB/G007993/1
The European Nutrigenomics Organisation; NuGO. Grant Number: CT2004-505944
Veni. Grant Number: 016.Veni.188.082