Lessons from the one-carbon metabolism: passing it along to the next generation

Abstract

During development, a fetus and its placenta must respond to a changing maternal environment to ensure normal growth is achieved and survival is maintained. The mechanisms behind developmental programming involve complex interactions between epigenetic and physiological processes, which are not well understood. Importantly, when programming goes awry, it puts the fetus at risk for disease later in life and may, in some instances, affect subsequent generations via epigenetic processes including DNA methylation. The one-carbon metabolism, which includes the folate, methionine and choline pathways, provides methyl groups necessary for DNA methylation and a normal epigenetic landscape. Accordingly, disruptions in this pathway affect placental development and function leading to altered fetal programming. Remarkably, recent studies have revealed that abnormal folate metabolism causes transgenerational effects probably through epigenetic inheritance. The epigenetic mechanisms behind this phenomenon are not well understood but they have important implications for the influence of the metabolic environment on epigenetic stability and non-genetic inheritance of disease. Importantly, there are increasing concerns that assisted reproductive technologies cause aberrant epigenetic profiles in embryos leading to abnormal fetal programming. How the negative epigenetic consequences of assisted reproduction treatment affect subsequent generations requires further investigation.

Keywords: assisted reproduction; fetal programming; folate metabolism; one-carbon metabolism; placenta; transgenerational epigenetic inheritance.