Epigenetics, Nutrition, and Growth

Author(s):
Berthold Koletzko, Mohammed El Sharkawy

Introduction

Convincing evidence has accumulated to demonstrate a variety of early developmental programming effects of environmental stimuli, including metabolic and nutritional exposures, on the developing organism, with lasting effects on later health, well-being, performance and disease risks up until old age. Exposure before and during pregnancy and in infancy and childhood appear to be particularly impactful. Epigenetic biochemical modifications of the human genome are a key mechanism regulating gene expression and hence biological functions, and could be one important mechanism underlying lasting metabolic programming effects of early exposures on later outcomes. We performed a search in the US National Library of Medicine (PubMed) with the search terms “(epigenetic*) AND ((nutrit*) OR (growth))” and filter “human” for the years 2020 and 2021, which revealed 2,641 hits. These were hand searched by B.K., and 13 publications were subjectively selected based on interest and relevance to human nutrition and growth. In the human studies found, DNA methylation (DNAm), a particularly stable epigenetic mechanism, was the most widely studied epigenetic modification. Most of the published studies were of an observational nature, whereas only relatively limited data are available on DNAm effects of randomized controlled interventions. Eight of the included studies relate to prenatal exposures, whereas five relate to postnatal life, reflecting our overall impression that more research focusses on studies performed in pregnancy and at birth. Exploring in more detail the impact of exposures during infancy and childhood may offer further opportunities, considering the potential for preventive interventions.

Association of maternal DNA methylation and offspring birthweight

Comments: This study tested the hypothesis that maternal factors and environment during pregnancy modulate birthweight by way of differential methylation of offspring DNA. The study assessed epigenome-wide methylation in maternal blood samples taken during the second half of pregnancy between 22 and 38 weeks of gestation of 114 women in the UK and related the data to birthweight of their 122 neonates (8 twins), adjusted for infant sex, maternal peripheral blood cell types, maternal BMI, smoking during pregnancy, and socioeconomic status. Replication of findings was attempted in a small cohort of 33 Swedish women with DNAm measured in blood samples obtained between 26 and 28 weeks of pregnancy. The study found eight CpG cytosine phosphate guanine sites (CpGs) located on or close to 11 genes associated with offspring birthweight, with statistical significance after false discovery rate correction, with six of eight CpGs modulating birthweight through effects on gestational age. Three of the eight CpGs showed marginal significance in the smaller replication cohort which are associated with four genes related to processes of endocytosis, membrane invagination, and vesicle organization. This study suggests that maternal or environmental factors might influence gestational age and birthweight through differential maternal DNAm. Targets for interventions reducing the risk of low or high birthweights should be identified to facilitate strategies for prevention of abnormal neonatal birthweights. The study also indicates the potential that measuring DNAm levels of maternal CpGs might have a diagnostic potential for identifying pregnancies at risk for abnormal birthweights.

Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: secondary analysis of a randomised control trial

Comments: Rates of gestational diabetes mellitus (GDM) are high and further increasing around the world, and it is associated with an increased risk for obesity and non-communicable diseases in offspring. This study examined whether maternal hyperglycemia during pregnancy led to altered DNAm in cord blood cells in a sample of 557 mother newborn dyads. Both GDM status and high maternal blood glucose were associated with modest changes in neonatal DNAm, which tended to be reduced with a randomized intervention applied during pregnancy targeting diet and physical activity.

Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring

Comments: This study explores the effect of a randomized controlled trial evaluating a lifestyle intervention including physical activity with and without advice on a low-energy Mediterranean-style diet in obese pregnant women on altered DNAm in cord blood in a subgroup of 232 neonates. Compared to the control group, offspring in the lifestyle intervention group had more lean body mass at birth along with differential cord blood DNAm at 379 sites. Genes associated with birth weight, obesity, adiposity, and type 2 diabetes were annotated to sites with altered DNAm in this study. DNAm at 17 sites were shown to partially mediate the effect of the lifestyle intervention on lean mass in the offspring. Together, these data provide evidence that the presented lifestyle intervention altered the epigenome of genes linked to metabolism and metabolic disease in offspring cord blood from pregnant mothers with obesity. The results support the hypothesis that intrauterine environment affected by physical activity and diet has programming effects of fetal metabolism and growth which may be mediated by epigenetic modifications.

Effect of maternal preconceptional and pregnancy micronutrient interventions on children’s DNA methylation: findings from the EMPHASIS study

Comments: Micronutrient deficiency before and during pregnancy is highly prevalent around the world and has been associated with lasting adverse effects on offspring health and development. This study reports on the effects of randomized interventions providing added micronutrients during pregnancy based on micronutrient-rich foods in India or a micronutrient supplement in Africa on DNAm in the children at school age. A number of CpG loci showed altered DNAm in the African children while no robust DNAm differences were identified in the Indian children, who received much lower micronutrient supplies with the food-based supplement. Further studies will need to explore whether the identified DNAm changes relate to relevant health outcomes.

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption

Comments: High intakes of caffeine in pregnancy have been associated with untoward effects in the offspring. Although the evidence base is less than satisfactory, as a precautionary measure pregnant women are widely advised to avoid high caffeine consumption and to limit coffee intake to about 1–2 cups per day. This large meta-analysis included more than 15,000 participants (61.4% women) of European and African-American ancestries from 15 adult cohort studies, with mean ages ranging from 41 to 79 years across cohorts. Coffee but not tea consumption was associated with multiple alterations of DNAm, with some related to pathways of coffee metabolism. These findings may offer further opportunities to explore mechanisms and effects of coffee consumption during pregnancy.

Effect of prenatal exposure to phthalates on epigenome-wide DNA methylations in cord blood and implications for fetal growth: the Hokkaido Study on Environment and Children’s Health

Comments: Phthalates are man-made chemicals that are added to polyvinyl chloride (PVC) to enhance flexibility, and to cosmetics and personal care products such as soaps, shampoos, and hair sprays to increase the durability of fragrances. They are also found as contaminants in food products. Humans are exposed to phthalates through ingestion, inhalation, skin absorption, and in the case of intravenous infusion due to the contact of infusates with PVC bags and lines. Phthalates are considered to be among the endocrine disrupting chemicals and have been associated with a variety of adverse health effects in animals and in humans, including adverse effects on fetal development. This study found prenatal exposure to di-2-ethylhexyl phthalate (DEHP), the most common phthalate compound in commercial uses, positively associated with DNAm in cord blood, while DNAm at CPGs associated with metabolic pathways was inversely correlated with the neonatal ponderal index. These findings are worrying as they indicate the potential of adverse effects of prenatal phthalate exposure on fetal growth mediated through epigenetic mechanisms.

Prenatal fine particulate matter exposure, placental DNA methylation changes, and fetal growth

Comments: Prenatal exposure to air pollution and particularly to fine particulate matter (PM2.5) has previously been associated with lower birth length and weight, abdominal circumference, and head circumference in several observational studies, but the underlying mechanisms are not well understood. This impressive study analyzed prenatal exposure to PM2.5 and longitudinal ultrasound measurements to characterize fetal growth, along with placental DNAm in 329 women participating in a cohort study in Shanghai, China. The results point to adverse effects of PM2.5 exposure on fetal growth in the second trimester of pregnancy as well as length at birth. PM2.5-associated changes were found in DNAm at CpG sites related to genes involved in reproductive development, immune responses, and energy metabolism. Hence, DNAm could be an underlying mechanism linking prenatal PM2.5 exposure and adverse effects on fetal growth and related health outcomes.

IGF1 gene is epigenetically activated in preterm infants with intrauterine growth restriction

Comments: The hormone IGF1 is formed mainly in the liver and is a key regulator of growth and growth-related metabolic pathways. The regulation of IGF1 secretion in early life has been related to programming effects on later health and disease risks. Therefore, better understanding of the regulation of IGF1 secretion is of great interest. DNAm of specific CpG sites associated with promoters of the IGF1 gene was previously reported as a potential epigenetic regulator of variation in circulating IGF1 and stature in growing children. Kantake at al. analyzed DNAm of six CpG sites in the IGF1 gene promoter P2 in 56 preterm infants with a gestational age from 23 to 31 weeks without or with intrauterine growth restriction. The findings show lower IGF1 P2 promoter methylation than reported in term infants and children, positive associations of DNAm of all six CpG sites with body weight and length at birth, and lower DNAm at all six CpG sites in IUGR than non-IUGR. The period after 32 weeks of gestation could be the critical time window for IGF1 gene methylation and hence for programming of later body size and health.

Association between breastfeeding and DNA methylation over the life course: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Comments: Breastfeeding is associated with a variety of differences in short- and long-term biological functions and health effects, as compared to formula feeding. This study explored differences in DNAm in peripheral blood cells in a sizeable cohort at three timepoints, i.e., at birth and at the ages of 7 and 15–17 years, respectively, by duration of any breastfeeding categorized as none, up to 3 months, 3–6 months, 6–12 months, or more than 12 months. Breastfeeding was associated with DNAm at the cg11414913 site at ages 7 and 15–17 years, and there was suggestive evidence of an association with DNAm at six additional CpGs at age 7 years. The associational effect estimates between ever breastfeeding and peripheral blood DNAm were generally small, and there was no indication of a dose-response relationship between breastfeeding duration and DNAm. Jointly with other findings (see below) the results suggests that breastfeeding can induce DNAm changes which might modulate lasting breastfeeding effects on relevant health outcomes.

Epigenome-wide association of infant feeding and changes in DNA methylation from birth to 10 years

Comments: This study examined whether infant feeding modes induce different DNAm changes between birth and age 10 years in groups that were exclusively breastfed or formula fed for at least 13 weeks after birth, or received mixed feeding with breastfeeding, formula, and solids before 13 weeks of age. The findings indicate significantly lower methylation in children exclusively formula fed for at least 3 months compared to children who were exclusively breastfed. An important opportunity arising from these findings is the exploration of potential upstream determinants of these differences, such as specific bioactive components of human milk, and the possible downstream effects on function and health outcomes in the recipient individuals.

Shared DNA methylation signatures in childhood allergy: the MeDALL study

Comments: This study analyzed DNAm in a large number of children at the ages of 4 and 8 years from combined cohort studies divided into discovery and replication subgroups. The authors identified 21 CpGs in whole blood associated with childhood allergy. Children with allergy showed consistently lower DNAm at two CpGs at 4 years of age and at 19 CpGs at 8 years of age shared between asthma, allergic rhinitis, eczema, and implicated eosinophils. It appears that postnatal changes in DNAm could have an important role in allergy development, and hence environmental and dietary factors that modulate DNAm at relevant CpGs could be of preventive value.

Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight

Comments: Rapid weight gain in the first year of life and the first 2 years of life has been consistently associated with an increased risk of overweight and obesity at later ages, and a variety of possible underlying mechanisms have been proposed. This study examined the association with peripheral blood cell DNAm at the ages of 7 and 10 years with both rapid weight gain in the first year of life and with conditional weight gain from low birthweight in a small subgroup of the British ALSPAC cohort study. The results show rapid weight gain in the first year of life associated with small but significant increases in DNAm at age 7 years at two CpG sites, with the highest levels of methylation at the cg11531579 locus at age 7 years in individuals who had early rapid weight gain and were overweight or obese at age 7 or 17 years (Fig. 1). The findings indicate that differential DNAm at 2 loci may be markers of weight gain in the first year of life and might serve as a biomarker of subsequent overweight or obesity in those who had early rapid weight gain if replicated in further studies.

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Comments: This impressive, large meta-analysis arose from the collaboration in the Pregnancy and Childhood Epigenetics (PACE) Consortium, the EU-funded LifeCycle Project, and the NutriProgram Project funded by EU member countries and underlines the great value of such collaborative initiatives. It evaluated the association of epigenome-wide DNAm with BMI in more than 4,000 children and adolescents. Little evidence of an association between DNAm and childhood or adolescent BMI was found, with DNAm at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, associated with BMI (Table 1). However, there was increasing enrichment and increasing point estimates of CpGs, previously reported in relation to adult adiposity, with increasing age. The results appear to indicate that DNAm differences are more a result of than a cause of obesity, but this hypothesis remains to be confirmed.

References
1 Robinson N, Brown H, Antoun E, Godfrey KM, Hanson MA, Lillycrop KA, et al. Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight. Clin Epigenetics. 2021 Jan;13(1):8.
2 Vehmeijer FOL, Küpers LK, Sharp GC, Salas LA, Lent S, Jima DD, et al. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome- wide association studies. Genome Med. 2020 Nov;12(1):105.