The influence of early environment and micronutrient availability on developmental epigenetic programming: lessons from the placenta

DNA methylation is the most commonly studied epigenetic mark in humans, as it is well recognised as a stable, heritable mark that can affect genome function and influence gene expression. Somatic DNA methylation patterns that can persist throughout life are established shortly after fertilisation when the majority of epigenetic marks, including DNA methylation, are erased from the pre-implantation embryo. Therefore, the period around conception is potentially critical for influencing DNA methylation, including methylation at imprinted alleles and metastable epialleles (MEs), loci where methylation varies between individuals but is correlated across tissues. Exposures before and during conception can affect pregnancy outcomes and health throughout life. Retrospective studies of the survivors of famines, such as those exposed to the Dutch Hunger Winter of 1944-45, have linked exposures around conception to later disease outcomes, some of which correlate with DNA methylation changes at certain genes. Animal models have shown more directly that DNA methylation can be affected by dietary supplements that act as cofactors in one-carbon metabolism, and in humans, methylation at birth has been associated with peri-conceptional micronutrient supplementation. However, directly showing a role of micronutrients in shaping the epigenome has proven difficult. Recently, the placenta, a tissue with a unique hypomethylated methylome, has been shown to possess great inter-individual variability, which we highlight as a promising target tissue for studying MEs and mixed environmental exposures. The placenta has a critical role shaping the health of the fetus. Placenta-associated pregnancy complications, such as preeclampsia and intrauterine growth restriction, are all associated with aberrant patterns of DNA methylation and expression which are only now being linked to disease risk later in life.