Effect of supplementation with methyl-donor nutrients on neurodevelopment and cognition: considerations for future research

Abstract

Pregnancy represents a critical period in fetal development, such that the prenatal environment can, in part, establish a lifelong trajectory of health or disease for the offspring. Poor nutrition (macro- or micronutrient deficiencies) can adversely affect brain development and significantly increase offspring risk for metabolic and neurological disease development. The concentration of dietary methyl-donor nutrients is known to alter DNA methylation in the brain, and alterations in DNA methylation can have long-lasting effects on gene expression and neuronal function. The decreased availability of methyl-donor nutrients to the developing fetus in models of poor maternal nutrition is one mechanism hypothesized to link maternal malnutrition and disease risk in offspring. Animal studies indicate that supplementation of both maternal and postnatal (early- and later-life) diets with methyl-donor nutrients can attenuate disease risk in offspring; however, clinical research is more equivocal. The objective of this review is to summarize how specific methyl-donor nutrient deficiencies and excesses during pre- and postnatal life alter neurodevelopment and cognition. Emphasis is placed on reviewing the current literature, highlighting challenges within nutrient supplementation research, and considering potential strategies to ensure robust findings in future studies.

Nutrients, Mitochondrial Function, and Perinatal Health

“…There is a connection between mitochondrial activity and methylation, due to the mitochondrial synthesis of formate, the folate cycle, and 1-C metabolism [ 6 ]. The 1-C metabolism provides methyl groups for methylation and the development of fetal DNA, but also one-carbon groups for at least 50 different methylation reactions (proteins, phospholipids, and nucleic acids), as well as for the synthesis of purines, thymidylate, creatine, phosphatidylcholine, and multiple hormones [ 87 , 88 , 89 ]. Mitochondria is the main site of formate production.…”

Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease

“…Low maternal periconceptional folic acid intake, especially in the context of a pesticide exposure as a “second hit” increases the risk of autism in the offspring by up to 2.5-fold (91). It will be important to consider the proper timing, dose and duration of dietary methyl donors with respect to brain development in light of the finding that these diets have potential for epigenetic modification of brain genes (42,92). Clinical trials of choline for vulnerable pediatric populations, such as children with fetal alcohol syndrome, have already begun and show positive effects on learning and memory behavior (93).…”

Maternal Dietary Factors and the Risk of Autism Spectrum Disorders: A Systematic Review of Existing Evidence

“…In addition, differences in DNA methylation have been noted in affected children and their parents, including global hypomethylation of DNA and hypermethylation of specific genes, such as CpG binding protein 2 (MeCP2), leading to downregulation of gene expression [Schaevitz & Berger‐Sweeney, 2012]. Some animal studies have also linked maternal and postnatal methyl‐donor nutrients supplements, which are essential for one‐carbon metabolism, with favorable offspring neurodevelopment outcomes, including autism‐related traits [McKee & Reyes, 2018]. In addition to potential influences on DNA methylation, nutrient roles in immune functioning, and inflammation represent another key pathway (particularly for Vitamin D, but also relevant for PUFAs and several other nutrients) [Hollis & Wagner, 2017; McDougle et al, 2015; Zerbo et al, 2015].…”