Synthetic Glucocorticoid Dexamethasone Inhibits Branching Morphogenesis in the Spiny Mouse Placenta1

Abstract

High levels of maternal glucocorticoids during pregnancy can alter the developmental trajectory of some fetal organs. These perturbations are often more profound for the male fetus and have been attributed to passage of glucocorticoids through the placenta. However, the effect of excess glucocorticoids on the placenta itself is less well understood and, particularly, whether this is affected by fetal sex. Expression of genes involved in placental patterning, apoptosis, and nutrient transfer, along with their response to maternal administration of dexamethasone (DEX), has previously been shown to be dependent on fetal sex in the spiny mouse. Here we describe the placental spatiotemporal expression of genes important for branching morphogenesis (WNT4, BMP4, GREM1, TGFB1, KDR, VEGFA). Furthermore, we report that compared to TGFB1 expression in the female labyrinth, expression of TGFB1 in the male labyrinth was higher, and earlier peaks in expression levels of VEGFA (Day 19 placenta [male] vs. Day 37 labyrinth [female]) and KDR (Day 19 placenta [male] vs. Day 20 labyrinth [female]) were observed. Administration of DEX to pregnant dams for 60 h commencing at mid-gestation caused significantly different, sex-related changes in expression of genes that were constitutively different before DEX treatment (e.g., KDR, TGFB1) and those that were not (i.e., VEGFA, WNT4). Similarly, some genes which displayed similar expression profiles across gestation for both sexes also showed similar responses to DEX (e.g., BMP4), while others did not (i.e., GREM1). These results showed that constitutive and glucocorticoid-induced changes in expression of genes involved in branching morphogenesis may be influenced by fetal/placental sex and that fundamental differences exist between a male and female placenta.