Table 3.

Studies linking maternal one-carbon metabolites or broader nutritional exposures to offspring DNA methylation and phenotype

Study	Exposure (exposure timing)	Offspring tissue analysed	Genes analysed	Phenotype investigated	Key findings (↑/↓: increased/decreased, ˜ associated with)
Azzi S et al.40	Pre-pregnancy BMI, vitamins B2, B3, B6, folate, B12 (3 months before conception and last trimester)	Cord blood	PLAGL1 (ZAC1)	Pre- and post-natal growth	↑Pre-pregnancy and last trimester vitamin B2 ˜ ↑ZAC1 methylation ↑Pre-pregnancy BMI ˜ ↑ZAC1 methylation ↑ZAC1 methylation index ˜ ↑estimated fetal weight at 32 weeks of gestation, ↑BMI z-scores at age 1 year
Drake AJ et al.62	Maternal diet: food group analysis (‘Early’ <20 weeks and ‘late’ >20 weeks of gestation)	Peripheral blood	IGF2, H19 ICR, HSD2, NR3C1	Birthweight, current height, weight, waist circumference, blood pressure	↑Meat/fish/vegetables and ↓bread/potato intake in late pregnancy ˜ ↑NR3C1 exon 1F methylation ↑Meat/fish intake in late pregnancy ˜ ↑HSD2 methylation ↑HSD2 methylation ˜ ↓neonatal ponderal index, ↑birthweight, ↑adiposity measures and ↑blood pressure in adulthood (age 40 years) ↑H19 ICR methylation ˜ ↓birth length, ↑weight, ↑waist circumference, ↑BMI and ↑blood pressure in adulthood ↑NR3C1 exon 1C methylation ˜ ↑waist circumference, ↑BMI, ↓blood pressure in adulthood
Godfrey KM et al.55	Maternal carbohydrate intake (2nd trimester)	Cord blood	RXRA, NOS3, SOD1, IL8, PIK3CD	Adiposity	↓Maternal carbohydrate intake ˜ ↑RXRA methylation ↑RXRA methylation ˜ ↑childhood fat mass, ↑% fat mass (at age 9 years)
Hoyo C et al.56	Maternal erythrocyte folate (1st trimester, median 12 weeks of gestation))	Cord blood	IGF2, H19, PEG1/MEST, PEG3, PLAGL1, MEG3-IG, PEG10/SGCE, NNAT, DLK1/MEG3	Birthweight	↑Folate levels ˜ ↓methylation at MEG3, PLAGL1, PEG3 and ↑methylation at IGF2 ↑Methylation at H19, PEG10/SGCE and PLAGL1 and ↓MEG3 methylation ˜ ↑birthweight MEG3 methylation ˜ strongest evidence for mediating association between folate and birthweight
Kühnen P et al.43	Maternal 1-carbon metabolites/season of conception (periconception)	Peripheral blood/MSH-positive neurons	POMC	Obesity/BMI	Gambian rainy season of conception and associated 1-carbon metabolites ∼ ↑POMC methylation ↑POMC methylation ∼ ↑BMI, ↑obesity in children and adults
Lin X et al.66	Maternal BMI, glucose, plasma fatty acids, plasma vitamin D, serum B12, B6, folate, iron, zinc, magnesium (3rd trimester; 26-28 weeks of gestation)	Cord blood	Epigenome-wide association study	Birthweight, size and adiposity at 4 years	↑Maternal omega-6 PUFA ˜ ↓cg25685359 (MIRLET7BHG) methylation ↓ MIRLET7BHG methylation ˜ ↑birthweight
Rijlaarsdam J et al.63	High-fat and -sugar diet (3rd trimester, 32 weeks of gestation)	Cord blood, peripheral blood at age 7 years	IGF2	ADHD	Prenatal highfat and high sugar diet ˜ ↑IGF2 methylation ↑IGF2 methylation ˜ ↑ADHD symptoms in early-onset persistent conduct (EOP) children age 7 years
Steegers-Theunissen RP et al.52	Maternal folic acid supplementation (periconception)	Peripheral blood	IGF2	Birthweight	↑Folic acid supplementation ˜ ↑IGF2 methylation at 17 months ↑IGF2 methylation ˜ ↓birthweight

ADHD, attention-deficit/hyperactivity disorder; BMI, body mass index; ICR, imprinting control region; PUFA, polyunsaturated fatty acids.