DNA methylation not only regulates gene expression, but is also critical during embryogenesis as it influences fetal programming and long-term disease susceptibility.  The availability of methyl groups from molecules, such as folic acid, during early pregnancy is vital to support one carbon metabolism and DNA methylation.  Yet little is known about the long-term impact of periconceptional folic acid supplementation on DNA methylation patterns in offspring later in life.  Work by Crider and colleagues addresses this void in our knowledge, and they report those results in the December 2022 issue of The Journal of Nutrition.

Mothers (n = 89, mean of 40-years old) and adolescents (n = 179, mean of 15 years old) from two sites involved in the Chinese Community Intervention Program of folic acid supplementation participated in this follow up study.  Saliva was collected to determine the interactions of periconceptual folic acid exposure (400 µg/d through first trimester), the 5,10-methylenetetrahydrofolate reductase-C667T genotype, and epigenome-wide DNA methylation.  Models included controls for offspring sex, geographic region, and background cell composition in the saliva.

No differences were found in the methylation patterns of adolescents, regardless of periconceptual folic acid supplementation after adjustment for the potential confounders.  The C667T genotype of 5,10-methylenetetrahydrofolate reductase gene did not affect the lack of association.  The authors concluded that periconceptual folic acid supplementation did not influence DNA methylation patterns among adolescents.

In an editorial, Lees-Murdock and Ward find the results of Crider and colleagues to be a critical contribution of data in a population not exposed to folic acid fortified foods.  They note the DNA methylation patterns of the offspring at birth may have been altered by folic acid supplementation, but the routinely low folate intakes of these populations may have prevented retention of any changes induced by folic acid exposure in early pregnancy.  They suggest randomized controlled trials should be conducted where explicit data for timing of exposure and the prevailing diet are known if we are to understand the long term impacts of periconceptual folic acid supplementation.


Crider KS, Wang A, Ling H, Potischman N, Bailey RL, Lichen Y, et al.  Maternal periconceptional folic acid supplementation and DNA methylation patterns in adolescent offspring.  Journal of Nutrition Volume 152, Issue 12, December 2022, Pages 2669-2676. https://doi.org/10.1093/jn/nxac184.

Lees-Murdock D, Ward M.  Can nutritional epigenomics explain persistent effects of periconceptional folic acid in the methylome?  Journal of Nutrition, Volume 152, Issue 12, December 2022, Pages 2636-2637. https://doi.org/10.1093/jn/nxac224.

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