This review summarizes evidence from cohort and intervention studies on the relationships between nutrition in early life, epigenetics, and lifelong health. Established links include maternal diet quality with conception rates, micronutrient sufficiency before and during pregnancy with preterm birth prevention, gestational vitamin D intake with offspring bone health, preconception iodine status with child IQ, adiposity with offspring obesity, and maternal stress with childhood atopic eczema. Animal studies demonstrate that early-life environmental exposures induce lasting phenotypic changes via epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, with DNA methylation of non-imprinted genes most extensively studied. Human data show that nutrition during pregnancy induces epigenetic changes associated with childhood obesity risk, such as Antisense long Non-coding RNA in the INK4 Locus (ANRIL, a long non-coding RNA) methylation variations linked to obesity and replicated across multiple populations. Emerging insights reveal that paternal nutrition and lifestyle also modify sperm epigenomics and influence offspring development. Although nutritional randomised trials in pregnancy remain limited, findings from the NiPPeR trial showed widespread preconception micronutrient deficiencies and indicated that maternal preconception and pregnancy nutritional supplementation can reduce preterm birth and early childhood obesity. The randomised trials UPBEAT and MAVIDOS have shown that nutritional intervention can impact offspring epigenetics. Postnatal nutritional exposures further influence offspring epigenetic profiles, exemplified by ALSPAC cohort findings linking rapid infant weight gain to later methylation changes and increased obesity risk. Together, these studies support a persistent impact of maternal and early-life nutrition on child health and development, underpinned by modifiable epigenetic processes.

In vitro fertilization (IVF) and its subset intracytoplasmic sperm injection (ICSI), are widely used medical treatments for conception. There has been controversy over whether IVF is associated with adverse short- and long-term health outcomes of offspring. As with other prenatal factors, epigenetic change is thought to be a molecular mediator of any in utero programming effects. Most studies focused on DNA methylation at gene-specific and genomic level, with only a few on associations between DNA methylation and IVF. Using buccal epithelium from 208 twin pairs from the Peri/Postnatal Epigenetic Twin Study (PETS), we investigated associations between IVF and DNA methylation on a global level, using the proxies of Alu and LINE-1 interspersed repeats in addition to two locus-specific regulatory regions within IGF2/H19, controlling for 13 potentially confounding factors. Using multiple correction testing, we found strong evidence that IVF-conceived twins have lower DNA methylation in Alu, and weak evidence of lower methylation in one of the two IGF2/H19 regulatory regions and LINE-1, compared with naturally conceived twins. Weak evidence of a relationship between ICSI and DNA methylation within IGF2/H19 regulatory region was found, suggesting that one or more of the processes associated with IVF/ICSI may contribute to these methylation differences. Lower within- and between-pair DNA methylation variation was also found in IVF-conceived twins for LINE-1, Alu and one IGF2/H19 regulatory region. Although larger sample sizes are needed, our results provide additional insight to the possible influence of IVF and ICSI on DNA methylation. To our knowledge, this is the largest study to date investigating the association of IVF and DNA methylation.

Early life environmental factors have been associated with altered predisposition to a variety of pathologies. A considerable literature examines pre- and postnatal factors associated with increased risk of cardiovascular, metabolic (i.e. insulin resistance, hyperlipidemia) and psychiatric disease, and the importance of hormonal programming. The brain is exquisitely sensitive to environmental inputs during development and the stress responsiveness of the hypothalamic–pituitary–adrenal (HPA) axis has been shown to be both up- and down-regulated by early life exposure to limited nutrition, stress, altered maternal behaviors, synthetic steroids and inflammation. It has been suggested that peri-natal programming of HPA axis regulation might therefore contribute to metabolic and psychiatric disease etiology. In addition, glucocorticoids play modulatory roles regulating many aspects of immune function, notably controlling both acute and chronic inflammatory responses. Neuroendocrine–immune communication is bidirectional, and therefore it is expected that environmental factors altering HPA regulation have implications for stress effects on immune function and predisposition to inflammation. The impact of pre- and postnatal factors altering immune function, stress responsivity and predisposition to inflammatory disease are reviewed. It is also examined whether the early ‘immune environment’ might similarly influence predisposition to disease and alter neuroendocrine function. Evidence indicating a role for early life inflammation and infection as an important factor programming the neuroendocrine–immune axis and altering predisposition to disease is considered.

There is substantial evidence which shows that constraints in the early life environment are an important determinant of risk of metabolic disease and CVD. There is emerging evidence that higher birth weight, which reflects a more abundant prenatal environment, is associated with increased risk of cancer, in particular breast cancer and childhood leukaemia. Using specific examples from epidemiology and experimental studies, this review discusses the hypothesis that increased susceptibility to CVD, metabolic disease and cancer have a common origin in developmental changes induced in the developing fetus by aspects of the intra-uterine environment including nutrition which involve stable changes to the epigenetic regulation of specific genes. However, the induction of specific disease risk is dependent upon the nature of the environmental challenge and interactions between the susceptibility set by the altered epigenome and the environment throughout the life course.