Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

Abstract

"Fetal programming" is a term used to describe how early-life experience influences fetal development and later disease risk. In humans, prenatal stress-induced fetal programming is associated with increased risk of preterm birth, and a heightened risk of metabolic and neurological diseases later in life. A critical determinant of this is the regulation of fetal exposure to glucocorticoids by the placenta. Glucocorticoids are the mediators through which maternal stress influences fetal development. Excessive fetal glucocorticoid exposure during pregnancy results in low birth weight and abnormalities in a number of tissues. The amount of fetal exposure to maternal glucocorticoids depends on the expression of HSD11B2, an enzyme predominantly produced by the syncytiotrophoblast in the placenta. This protects the fetus by converting active glucocorticoids into inactive forms. In this review we examine recent findings regarding placental HSD11B2 that suggest that its epigenetic regulation may mechanistically link maternal stress and long-term health consequences in affected offspring.

Keywords: 11β-hydroxysteroid dehydrogenase type-2; epigenetic; fetal outcome; placenta; prenatal stress.

Figure 1. The placental HSD11B2 shield. (A) During pregnancy, the placenta acts as a critical regulator that limits fetal exposure to maternal glucorticoids. (B) Cross sectional image of the placenta. Blood travels from the fetus through the umbilical arteries (blue). Blood is carried to the chorionic villi, where exchange of nutrients and waste products with the mother occurs. The chorionic villi are made up of two epithelial layers, the syncytiotrophoblast and the cytotrophoblast. (C) Longitudinal section of the chorionic villi. HSD211B2 is expressed strongly in the syncytiotrophoblast and to a lesser extent in the cytotrophoblast, where it converts cortisol into inactive cortisone, thereby protecting the fetus from excessive cortisol exposure.