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.

Dieuwertje E Kok,Chris T Evelo,Rebecca C Richmond,John C Mathers,Natassia Robinson,Jill A Mckay,Michiel Adriaens,Dianne Ford

doi:10.1002/mnfr.202100789

Abstract

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. 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). 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.

Highlights

The Developmental Origins of Health and Disease (DOHaD) hypothesis argues for a causal relationship between early-life environment and disease risk in later-life [1]
We used a novel hypothesis-generating approach to investigate whether DNA methylation changes associated with maternal folate status or folic acid intake during development are likely to persist into adulthood
Whilst many studies have demonstrated the influence of maternal folate status alone during pregnancy on DNA methylation in the offspring [24,25,26,27,28], to the best of our knowledge, none have used genome-wide analysis to investigate potentially persistent changes across the life course

Summary

Introduction

The Developmental Origins of Health and Disease (DOHaD) hypothesis argues for a causal relationship between early-life environment and disease risk in later-life [1]. To the best of our knowledge, no study has used genome-wide assessment to investigate if observed changes in methylation as a result of maternal folate depletion alone during pregnancy are likely to persist from development into adulthood, and with potential to influence later-life health. We first analysed and compared data examining the influence of maternal folate depletion on offspring DNA methylation during development and in adulthood in a mouse model to uncover methylation changes, and biological pathways and processes potential affected by those methylation changes, mostly likely to be persistent across the life course. In our translation ‘replication’ phase we examined data from two human studies, a meta-analysis and a randomised controlled trial (RCT), which investigated the relationships between maternal folate status/supplementation during pregnancy and DNA methylation of offspring at birth and in adulthood, respectively. Hypergeometric tests were carried out using the online calculator to assess the probability that differences in methylation at CpG sites associated with maternal folate status or intake across both studies was not due to chance (p

Results

Discussion

Conflict of Interest Statement