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

Abstract

Scope: 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.

Influence of maternal folate depletion on Art3 DNA methylation in the murine adult brain; potential consequences for brain and neurocognitive health

“…However, for Art3 , hypomethylation across the locus was consistent at all CpGs investigated, which makes it unlikely that this finding is due to chance. In addition to our previous report of Art3 hypermethylation in the liver of offspring born to folate-depleted mothers, hypermethylation of the promoter of this gene was observed in cord blood and saliva of the offspring of mothers with lower folate status [ 55 ]. Although here we have observed an opposing direction of methylation change in brain tissue, taken together, these data suggest that methylation of Art3 is particularly susceptible to maternal folate status in multiple tissues and across species.…”

“…Here we quantified DNA methylation of five target genes in the sub-cortical brain tissue of adult mice whose mothers had been depleted of folate during pregnancy and lactation. These target genes were selected as they have previously been found to have altered methylation in other tissues in association with early-life folate exposure in both mice and humans, and, for 4/5 genes, also in adulthood [ 47 , 48 , 50 , 51 , 55 ]. Moreover, our previous investigation suggested these genes may potentially influence neurocognitive outcomes [ 55 ].…”

“…These target genes were selected as they have previously been found to have altered methylation in other tissues in association with early-life folate exposure in both mice and humans, and, for 4/5 genes, also in adulthood [ 47 , 48 , 50 , 51 , 55 ]. Moreover, our previous investigation suggested these genes may potentially influence neurocognitive outcomes [ 55 ]. Given the evidence that early-life folate status may influence neurocognitive outcomes in offspring [ 28–37 ], we hypothesized that altered DNA methylation of these genes within brain tissue may mediate this relationship.…”

“…Previously we uncovered five gene promoters ( Art3, Rsp16, Tspo, Wnt16 , and Pcdhb6 ) which were modestly hypermethylated in response to low maternal folate during early development and in adulthood across both mouse (liver) and human studies (cord blood and/or saliva) [ 55 ]. The function of most of these genes implies that they are involved in neurocognition (see Table 1 for details), and therefore may represent persistent, latent epigenetic changes that have the potential to influence neurocognitive outcomes in later life.…”

Folate depletion alters mouse trophoblast stem cell regulationin vitro

“…We propose two hypotheses (not necessarily mutually exclusive): 1) folate depletion drives TSC differentiation towards a syncytiotrophoblast cell fate at the expense of TGC subtypes. This might result from altered DNA methylation causing misexpression of genes responsible for lineage decisions [22]; 2) TGCs form yet DNA endoreduplication [23] is repressed by low folate (and consequently, low thymidine [24]) levels resulting in altered amplification and transcription of TGC-specific genes [25].…”