Prenatal dexamethasone exposure exerts sex-specific effect on placental oxygen and nutrient transport ascribed to the differential expression of IGF2

Abstract

Background: Clinical studies have showed that dexamethasone exposure during pregnancy could cause fetal growth retardation, but the mechanism by which prenatal dexamethasone exposure influences placental nutrient transport is still unclear. This study investigated the impacts of prenatal dexamethasone on the placental oxygen and nutrient transport.Methods: Pregnant Wistar rats were subcutaneously administered with dexamethasone from day 9 to day 20 of gestation at 0.2 or 0.8 mg/kg•d. Pregnant rats were sacrificed on gestational day 20. The placental tissue was collected for analysis.Results: Prenatal dexamethasone exposure (PDE) declined the fetal weight and increased the intrauterine growth retardation (IUGR) rate in a dose-dependent manner. The total placental volume and the length, density and surface area of fetal capillaries in the labyrinth zone reduced in a dose-dependent manner. In addition, the thickness of syncytial membrane dose-dependently increased, resulting in a dose-dependent decrease in oxygen diffusion capacity. Furthermore, after PDE, the nutrient transport area and oxygen diffusion capacity of male placenta were lower than that of female placenta. The mRNA and protein expression of placental nutrient transporters including glucose transporter 1 (GLUT1), glucose transporter 3 (GLUT3), L-type amino acid transporter 1 (LAT1), lipoprotein lipase (LPL) and scavenger receptor class B type 1 (SRB1) increased in female placenta. However, in male placenta, the expression of LAT1, LPL and SRB1 was significantly decreased and GLUT1 and GLUT3 have a decrease trend. We further investigated the expression of insulin-like growth factor 1 (IGF1) and insulin-like growth factor 2 (IGF2) related to placental and fetal growth and development. Our study showed that the expression of IGF1 was significantly decreased both in male and female placentas after PDE. But the expression of IGF2 was significantly increased in female placentas while significantly decreased in male placentas. Conclusions:Our study shows prenatal dexamethasone exposure exerts sex-specific influence on the placental oxygen and nutrient transport. This might be ascribed to the differential expression of IGF2 after PDE. These findings provide evidence on the dexamethasone-induced toxicity to the placenta and fetal development.

Let’s Talk about Placental Sex, Baby: Understanding Mechanisms That Drive Female- and Male-Specific Fetal Growth and Developmental Outcomes

“…Similar to the findings of Hewitt et al [72], dexamethasone exposure induced fetal growth restriction in both sexes, but reduced junctional zone area in females only [74]. This female-specific placental adaptation was associated with changes in the expression of certain GR isoforms and increased expression of apoptotic genes [75]. In contrast, corticosterone had no direct impact on fetal or placental growth but following removal of the glucocorticoid challenge male placentae had a significant increase in total placental weight that was thought to be due to an increase in junctional zone, but decrease in labyrinth zone, volume.…”

“…In mice, Cuffe et al performed two separate studies [74,75] to investigate if exposure to synthetic or natural glucocorticoids induced similar sex-specific differences to the developing placenta. Similar to the findings of Hewitt et al [72], dexamethasone exposure induced fetal growth restriction in both sexes, but reduced junctional zone area in females only [74].…”

“…Changes in GR expression and localisation may contribute to sex-specific differences in growth outcomes. Placentae from IUGR females have been shown to increase nuclear GRα expression in both extravillous trophoblast (EVT) and syncytiotrophoblast cells (as measured by immunohistochemistry in humans) [84] and increased nuclear expression of GRαD1-3 isoforms (as measured by Western blot in mice) [75]. Unlike in females, growth restriction in males was associated with increased GRβ expression in humans [84], and a decrease in the activity of GrαA in mice, as determined by its cytoplasmic sequestration [75].…”

“…Placentae from IUGR females have been shown to increase nuclear GRα expression in both extravillous trophoblast (EVT) and syncytiotrophoblast cells (as measured by immunohistochemistry in humans) [84] and increased nuclear expression of GRαD1-3 isoforms (as measured by Western blot in mice) [75]. Unlike in females, growth restriction in males was associated with increased GRβ expression in humans [84], and a decrease in the activity of GrαA in mice, as determined by its cytoplasmic sequestration [75]. These sex-specific differences in the placental responsivity to changes in glucocorticoids favour the work conducted in human population studies of maternal asthma associated with sex-specific intrauterine growth outcomes.…”

Congenital adrenal hyperplasia with homozygous and heterozygous mutations: a rare family case report

“…Most pregnant women carrying an identified 46,XX CAH fetus who go ahead with PreDex therapy at an early stage of gestation (before 6 weeks) take it until delivery. However, its use before delivery is controversial because it has been reported to reduce fetal weight and increase the intrauterine growth retardation rate in a dose-dependent manner [ 27 ]. Other glucocorticoids may also have similar adverse consequences, with hydrocortisone and fludrocortisone shown to be negatively associated with growth velocity [ 28 ].…”