Kok Dieuwertje E, Saunders Rachael, Nelson Andrew, Smith Darren, Ford Dianne, Mathers John C, McKay Jill A
Division of Human Nutrition and Health, Wageningen University & Research, P.O. Box 17, 6700 AA Wageningen Stippeneng 4, 6708 WE Wageningen Wageningen Campus l Building 124 (Helix), Wageningen, The Netherlands.
Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Northumberland Building, Newcastle Upon Tyne, NE1 8ST, United Kingdom.
Mutagenesis. 2024 Apr 24;39(3):196-204. doi: 10.1093/mutage/geae007.
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.
健康与疾病的发育起源假说认为，生命早期的环境会影响整个生命历程中的健康结果。特别是，包括DNA甲基化在内的表观遗传标记被认为是环境暴露影响后期健康的关键机制。孕期及孕前充足的母体叶酸状态对于预防神经管缺陷至关重要，但越来越多的数据表明，生命早期的叶酸暴露可能也会影响儿童期乃至之后的神经认知结果。由于叶酸是DNA甲基化所需甲基供体的关键来源，我们推测DNA甲基化可能是母体叶酸影响神经认知结果的一种中介机制。我们采用亚硫酸氢盐测序法，测定了孕期（约19 - 21天）和哺乳期（平均22天）叶酸缺乏（n = 5，0.4毫克叶酸/千克饮食）的母鼠所产后代成年小鼠脑组织中五个基因（Art3、Rsp16、Tspo、Wnt16和Pcdhb6）的DNA甲基化情况，并与对照组（n = 6，2毫克叶酸/千克饮食）进行比较。选择这些基因是因为之前发现它们启动子的甲基化在小鼠和人类的整个生命历程中会因母体叶酸摄入而改变，且它们与神经认知结果可能存在关联。母体叶酸缺乏与28周龄成年小鼠皮质下脑组织中Art3基因低甲基化显著相关（平均降低6.2%，P = 0.03）。对于其他基因，叶酸缺乏组和对照组之间未发现统计学上的显著差异。鉴于其与神经认知结果的关联，我们认为Art3在生命历程脑健康背景下值得进一步研究。我们发现了一个潜在的生物标志物，一旦在可获取的生物样本和人类环境中得到验证，可能有助于追踪生命早期叶酸暴露对后期神经认知健康的影响，并有可能用于开发和监测干预措施的效果。
