Epigenetic Effect of Maternal Methyl-Group Donor Intake on Offspring's Health and Disease.

Maternal exposure to some dietary and environmental factors during embryonic development can affect offspring's phenotype and, furthermore, the risk of developing diseases later in life. One potential mechanism responsible for this early programming may be the modification of the epigenome, such as DNA methylation. Methyl-group donors are essential for DNA methylation and are shown to have an important role in fetal development and later health. The main goal of the present review is to summarize the available literature data on the epigenetic effect (DNA methylation) of maternal methyl-group donor availability on reproductivity, perinatal outcome, and later health of the offspring. In our literature search, we found evidence for the association between alterations in DNA methylation patterns caused by different maternal methyl-group donor (folate, choline, methionine, betaine) intake and reproductivity, birth weight, neural tube defect, congenital heart defect, cleft lip and palate, brain development, and the development of obesity and associated non-communicable diseases in later life. We can conclude that maternal methyl-group donor availability could affect offspring's health via alterations in DNA methylation and may be a major link between early environmental exposure and the development of diseases in the offspring. However, still, further studies are necessary to confirm the associations and causal relationships.

The effect of paternal methyl-group donor intake on offspring DNA methylation and birth weight.

Most nutritional studies on the development of children focus on mother-infant interactions. Maternal nutrition is critically involved in the growth and development of the fetus, but what about the father? The aim is to investigate the effects of paternal methyl-group donor intake (methionine, folate, betaine, choline) on paternal and offspring global DNA (hydroxy)methylation, offspring IGF2 DMR DNA methylation, and birth weight. Questionnaires, 7-day estimated dietary records, whole blood samples, and anthropometric measurements from 74 fathers were obtained. A total of 51 cord blood samples were collected and birth weight was obtained. DNA methylation status was measured using liquid chromatography-tandem mass spectrometry (global DNA (hydroxy)methylation) and pyrosequencing (IGF2 DMR methylation). Paternal betaine intake was positively associated with paternal global DNA hydroxymethylation (0.028% per 100 mg betaine increase, 95% CI: 0.003, 0.053, P=0.03) and cord blood global DNA methylation (0.679% per 100 mg betaine increase, 95% CI: 0.057, 1.302, P=0.03). Paternal methionine intake was positively associated with CpG1 (0.336% per 100 mg methionine increase, 95% CI: 0.103, 0.569, P=0.006), and mean CpG (0.201% per 100 mg methionine increase, 95% CI: 0.001, 0.402, P=0.049) methylation of the IGF2 DMR in cord blood. Further, a negative association between birth weight/birth weight-for-gestational age z-score and paternal betaine/methionine intake was found. In addition, a positive association between choline and birth weight/birth weight-for-gestational age z-score was also observed. Our data indicate a potential impact of paternal methyl-group donor intake on paternal global DNA hydroxymethylation, offspring global and IGF2 DMR DNA methylation, and prenatal growth.

Maternal Methyl-Group Donor Intake and Global DNA (Hydroxy)Methylation before and during Pregnancy.

It is still unclear to which extent methyl-group intake during pregnancy can affect maternal global DNA (hydroxyl)methylation. Pregnancy methylation profiling and its link with methyl-group intake in a healthy population could enhance our understanding of the development of pregnancy related disorders. One hundred forty-eight women were enrolled in the MANOE (MAternal Nutrition and Offspring's Epigenome) study. Thiry-four women were enrolled before pregnancy and 116 during the first trimester of pregnancy. Global DNA (hydroxy)methylation in blood using LC-MS/MS and dietary methyl-group intake (methionine, folate, betaine, and choline) using a food-frequency questionnaire were estimated pre-pregnancy, during each trimester, and at delivery. Global DNA (hydroxy)methylation levels were highest pre-pregnancy and at weeks 18-22 of pregnancy. We observed a positive relation between folic acid and global DNA methylation (p = 0.04) and hydroxymethylation (p = 0.04). A high intake of methionine pre-pregnancy and in the first trimester showed lower (hydroxy)methylation percentage in weeks 11-13 and weeks 18-22, respectively. Choline and betaine intake in the first weeks was negatively associated with hydroxymethylation. Women with a high intake of these three methyl groups in the second and third trimester showed higher hyrdoxymethylation/methylation levels in the third trimester. To conclude, a time trend in DNA (hydroxy)methylation was found and women with higher methyl-group intake showed higher methylation in the third trimester, and not in earlier phases of pregnancy.

Methyl group donors abrogate adaptive responses to dietary restriction in C. elegans.

BACKGROUND: Almost all animals adapt to dietary restriction through alternative life history traits that affect their growth, reproduction, and survival. Economized management of fat stores is a prevalent type of such adaptations. Because one-carbon metabolism is a critical gauge of food availability, in this study, we used Caenorhabditis elegans to test whether the methyl group donor choline regulates adaptive responses to dietary restriction. We used a modest dietary restriction regimen that prolonged the fecund period without reducing the lifetime production of progeny, which is the best measure of fitness. RESULTS: We found that dietary supplementation with choline abrogate the dietary restriction-induced prolongation of the reproductive period as well as the accumulation and delayed depletion of large lipid droplets and whole-fat stores and increased the survival rate in the cold. By contrast, the life span-prolonging effect of dietary restriction is not affected by choline. Moreover, we found that dietary restriction led to the enlargement of lipid droplets within embryos and enhancement of the cold tolerance of the progeny of dietarily restricted mothers. Both of these transgenerational responses to maternal dietary restriction were abrogated by exposing the parental generation to choline. CONCLUSIONS: In conclusion, supplementation with the methyl group donor choline abrogates distinct responses to dietary restriction related to reproduction, utilization of fat stored in large lipid droplets, cold tolerance, and thrifty phenotypes in C. elegans.