The clinical significance of periconceptional folic acid supplementation (FAS) in the prevention of neonatal neural tube defects (NTDs) has been recognized for decades. Epidemiological data and experimental findings have consistently been indicating an association between folate deficiency in the first trimester of pregnancy and poor fetal development as well as offspring health (i.e., NTDs, isolated orofacial clefts, neurodevelopmental disorders). Moreover, compelling evidence has suggested adverse effects of folate overload during perinatal period on offspring health (i.e., immune diseases, autism, lipid disorders). In addition to several single-nucleotide polymorphisms (SNPs) in genes related to folate one-carbon metabolism (FOCM), folate concentrations in maternal serum/plasma/red blood cells must be considered when counseling FAS. Epigenetic information encoded by 5-methylcytosines (5mC) plays a critical role in fetal development and offspring health. S-adenosylmethionine (SAM), a methyl donor for 5mC, could be derived from FOCM. As such, folic acid plays a double-edged sword role in offspring health via mediating DNA methylation. However, the underlying epigenetic mechanism is still largely unclear. In this review, we summarized the link across DNA methylation, maternal FAS, and offspring health to provide more evidence for clinical guidance in terms of precise FAS dosage and time point. Future studies are, therefore, required to set up the reference intervals of folate concentrations at different trimesters of pregnancy for different populations and to clarify the epigenetic mechanism for specific offspring diseases.
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We thank Jun-Ting Zhou for preparing Fig. 3B (Department of Clinical Laboratory, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071, China). We also would like to appreciate Professor Wei Zhang (Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, USA) for manuscript review.
This research was supported by grants from the National Natural Science Foundation of China (81771543, 81972009), and Health Commission of Hubei Province Scientific Research Project (WJ2019C002, WJ2019H005).
Conflict of Interest
The authors declared that they have no conflicts of interest.
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Liu, HY., Liu, SM. & Zhang, YZ. Maternal Folic Acid Supplementation Mediates Offspring Health via DNA Methylation. Reprod. Sci. 27, 963–976 (2020). https://doi.org/10.1007/s43032-020-00161-2
- Folic acid supplementation
- DNA methylation
- Offspring health