Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

Abstract

A poorly functioning placenta results in impaired exchanges of oxygen, nutrition, wastes and hormones between the mother and her fetus. This can lead to restriction of fetal growth. These growth restricted babies are at increased risk of developing chronic diseases, such as type-2 diabetes, hypertension, and kidney disease, later in life. Animal studies have shown that growth restricted phenotypes are sex-dependent and can be transmitted to subsequent generations through both the paternal and maternal lineages. Altered epigenetic mechanisms, specifically changes in DNA methylation, histone modifications, and non-coding RNAs that regulate expression of genes that are important for fetal development have been shown to be associated with the transmission pattern of growth restricted phenotypes. This review will discuss the subsequent health outcomes in the offspring after growth restriction and the transmission patterns of these diseases. Evidence of altered epigenetic mechanisms in association with fetal growth restriction will also be reviewed.

Keywords: cardiometabolic disease; epigenetic mechanisms; intrauterine growth restriction; kidney dysfunction; small for gestational age; transgenerational transmission; uteroplacental insufficiency.

Figure 1

Small for gestational age (SGA) babies who were exposed to intrauterine insults have altered epigenetic mechanisms and aberrant physiological changes, predisposing them to an increased risk of developing various chronic diseases later in life (–, –40).

Figure 2

Intrauterine growth restriction (IUGR) phenotypes are sex-specific and can be transmitted to subsequent generations, including the restricted F1 and non-restricted F2 and F3 offspring (intergenerational). Similar to human studies, altered epigenetic mechanisms such as non-coding RNA modifications, DNA methylation, and histone modifications were also found in these offspring. Results obtained from differerent rat and mouse IUGR models (, –, , –70).