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

Abstract

The developmental origins of health and disease hypothesis suggests early life environment impacts on health outcomes throughout the lifecourse. In particular, epigenetic marks, including DNA methylation, are thought to be key mechanisms through which environmental exposures programme later-life health. Adequate maternal folate status before and during pregnancy is essential in the protection against neural tube defects, but data are emerging that suggest early life folate exposures may also influence neurocognitive outcomes in childhood and, potentially, thereafter. Since folate is key to the supply of methyl donors for DNA methylation, we hypothesise that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of 5 genes (Art3, Rsp16, Tspo, Wnt16, Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n=5, 0.4mg folic acid/kg diet) during pregnancy (~19-21 days) and lactation (mean 22 days) compared with controls (n=6, 2mg folic acid/kg diet). Genes were selected as methylation of their promoters had previously been found to be altered by maternal folate intake in mice and humans across the lifecourse, and because they have potential associations with neurocognitive outcomes. Maternal folate depletion was significantly associated with Art3 gene hypomethylation in subcortical brain tissue of adult mice at 28 weeks of age (mean decrease 6.2%, p=0.03). For the other genes no statistically significant differences were found between folate depleted and control groups. Given its association with neurocognitive outcomes, we suggest Art3 warrants further study in the context of lifecourse brain health. We have uncovered a potential biomarker which, once validated in accessible biospecimens and human context, may be useful to track the impact of early life folate exposure on later life neurocognitive health, and potentially be used to develop and monitor the effects of interventions.