Background: Current clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS; dexamethasone or betamethasone) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development. This highlights a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only in tissues with specific enzymes, particularly carboxylesterase 1 and 2 (CES1, CES2), whose expression and activity are high in lungs but not the brain. However, the human placenta expresses CES, and might therefore convert CIC to its GR-activating metabolite des-CIC. This may preclude CIC use as a novel GR-agonist before preterm birth, since the fetus would be systemically exposed to des-CIC, causing GR activation in the brain and lung. We therefore investigated CES isoform expression and conversion of CIC to des-CIC in human placentas collected during the second trimester (Tri2), and at preterm and term birth.
Methods: Differential expression analysis was performed in Tri2 (n=27), preterm (n=34), and term (n=40) placentas using the DESeq2 R-package. A log fold change (logFC) of ±1 with a false discovery rate (FDR) of 0.05 was considered biologically significant. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n=7, preterm n=26, term n=20) using functional assays developed for Liquid Chromatography with tandem mass spectrometry. Data was analysed using KW-ANOVA.
Results: CES1 was higher in Tri2 compared with preterm (logFC=1.31, FDR= 1.74E-09) and term (logFC=1.61, FDR= 7.86E-15) placentas. CES2 expression did not differ between gestational ages. Human placenta converted CIC to des-CIC; however, activity was not impacted by gestational age.
Conclusion: Conversion of CIC to des-CIC by the human placenta highlights a need for preclinical studies to assess the efficacy of novel delivery methods to achieve GR activation in the developing lung but not brain.