TY - JOUR
T1 - Influence of maternal folate depletion on Art3 DNA methylation in the murine adult brain
T2 - potential consequences for brain and neurocognitive health
AU - Kok, Dieuwertje E.
AU - Saunders, Rachael
AU - Nelson, Andrew
AU - Smith, Darren
AU - Ford, Dianne
AU - Mathers, John C.
AU - McKay, Jill A.
N1 - Funding information: This work was supported by the Biotechnology and Biological Sciences Research Council [BB/G007993/1 to J.C.M. and D.F.] and United Kingdom Environmental Mutagen Society [Small Grants scheme for Feasibility and Pilot Studies to J.A.M., D.E.K. and E.G.] and NUTRAN at Northumbria University [Seed funding to J.A.M., D.S., D.F.].
PY - 2024/5/1
Y1 - 2024/5/1
N2 - The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. 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 hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19–21 days) and lactation (mean 22 days) compared with controls (n = 6, 2 mg 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 life course, 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 = .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 that, 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.
AB - The developmental origins of health and disease hypothesis suggest early-life environment impacts health outcomes throughout the life course. 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 hypothesize that DNA methylation may be a mediating mechanism through which maternal folate influences neurocognitive outcomes. Using bisulphite sequencing, we measured DNA methylation of five genes (Art3, Rsp16, Tspo, Wnt16, and Pcdhb6) in the brain tissue of adult offspring of dams who were depleted of folate (n = 5, 0.4 mg folic acid/kg diet) during pregnancy (~19–21 days) and lactation (mean 22 days) compared with controls (n = 6, 2 mg 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 life course, 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 = .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 that, 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.
KW - Animals
KW - Brain/metabolism
KW - DNA Methylation/drug effects
KW - Epigenesis, Genetic
KW - Female
KW - Folic Acid
KW - Folic Acid Deficiency/genetics
KW - Male
KW - Mice
KW - Pregnancy
KW - Prenatal Exposure Delayed Effects/genetics
UR - http://www.scopus.com/inward/record.url?scp=85191544295&partnerID=8YFLogxK
U2 - 10.1093/mutage/geae007
DO - 10.1093/mutage/geae007
M3 - Article
C2 - 38417824
SN - 0267-8357
VL - 39
SP - 196
EP - 204
JO - Mutagenesis
JF - Mutagenesis
IS - 3
M1 - geae007
ER -