Dose-, stage- and sex- difference of prenatal prednisone exposure on placental morphological and functional development.

Abstract

Prednisone, a synthetic glucocorticoid, is commonly used to treat autoimmune diseases in pregnant women. However, some studies suggest that the use of prednisone during pregnancy may lead to adverse pregnancy outcomes. In this study, we established PPE mouse models at different doses (0.25, 0.5, 1.0mg/kg·d) and different stages (whole pregnancy, early pregnancy and middle-late pregnancy) and determined outcomes on the placenta and fetus. The results of our study indicated that at the highest dose of 1mg/kg PPE using a GD 0-18 dosing regime, PPE caused placental morphological changes measured as a decrease in placental weight relative to controls and a decrease in the placenta junctional zone (JZ)/labyrinth zone (LZ) ratio. No changes were observed on the fetuses for number of live, stillborn, and absorbed fetuses between the experimental groups and the control group. In the placentas at some doses, there were decreases in cell proliferation markers measured at the RNA and protein level by Western blot and increased apoptosis. Measures of gene expression at the mRNA level showed altered nutrients (including glucose, amino acid, and cholesterol) transport gene expressions with the most significant change associated with the male placentas at high-dose and whole pregnancy PPE group. It was further found that PPE led to the inhibition of the insulin-like growth factor 2 (IGF2)/insulin-like growth factor 1 receptor (IGF1R) signaling pathway, which was well correlated with the indicators of cell proliferation, syncytialization and nutrient (glucose and amino acid) transport indices. In conclusion, PPE can alter placental morphology and nutrient transport function, with differences in effect related to dose, stage and gender. Differential gene expressions measured for genes of the IGF2/IGF1R signaling pathway suggested this pathway may be involved in the effects seen with PPE. This study provides a theoretical and experimental basis for enhancing the understanding of the effects of prednisone use on placenta during human pregnancy but does not currently raise concerns for human use as effects were not seen on the fetuses and while the effects on cell proliferation are informative they were inconsistent and the differential effects on female and male placentas unexplained suggesting that further work is required to elucidate if these findings have relevance for human use of PPE during pregnancy.