ABSTRACT
The placenta has a central role not only in determining immediate pregnancy outcomes but also in mediating the process of fetal programming and subsequent development of disease later in life. Adverse maternal conditions, including level and type of nutrition, affect placental function and directly or indirectly program the fetus via epigenetic modications in the placenta and fetus. Epigenetic modications include histone methylation and acetylation, which, in turn, may facilitate differential DNA methylation and alter gene expression. The sexual dimorphism seen in epigenetic changes in placenta may underlie the different responses of male and female fetuses to the intrauterine environment. The zygote uniquely undergoes global demethylation early in gestation and is then remethylated, but the trophectoderm, which forms the placenta, is remethylated to a level below that of somatic tissues. The level and composition of nutrients and metabolic health (obesity, diabetes) can effect epigenetic changes in many organs. Currently, there is little direct evidence for nutrients affecting placental epigenetics; however, abundant data show altered epigenetics with adverse pregnancy outcomes, including diabetes, undernutrition and overnutrition, preeclampsia, and intrauterine growth restriction (IUGR). The mechanisms linking nutrition and epigenetic changes are slowly being revealed, including those between cellular metabolism and methylation-demethylation via the regulation of ten-eleven translocation enzymes by α-ketoglutarate, a product of the citric acid cycle. As the supply of methyl donors by the one-carbon cycle can regulate DNA methylation, manipulation of methyl donors may epigenetically alter fetal metabolic phenotype.
