PDE4B-associated regulation of placental HSD11B2 in fetal growth restriction in a prenatal caffeine exposure model.

Caffeine, which is widely present in various medications and food products, has been epidemiologically associated with fetal growth restriction (FGR). Hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) is a key placental enzyme implicated in FGR induced by adverse prenatal exposures. This study investigates the regulation of placental HSD11B2 and explores potential modifiable mechanisms. Our findings demonstrated that environmentally relevant concentrations of caffeine inhibits the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway, leading to decreased specificity protein 1 (SP1) expression and increased early growth response factor 1 (EGR1) expression. These changes altered histone modifications in the HSD11B2 promoter (lower H3K9ac, higher H3K9me2), and decreased intracellular cortisol. Cortisol were observed to inhibit HSD11B2 expression. Under combined exposure, however, cortisol attenuated caffeine-induced inhibition of the cAMP/PKA/HSD11B2 pathway. This effect involved upregulation of the glucocorticoid receptor (GR) and miR-26a-5p and downregulation of phosphodiesterase 4B (PDE4B), thus modulating the SP1/HSD11B2 axis. Finally, oral administration of roflumilast (a PDE4 inhibitor) to mice with prenatal caffeine exposure restored fetal body weight and improved placental cAMP/PKA/SP1/HSD11B2 pathway activity. This study provides theoretical and experimental evidence for the self-regulatory function of the placental glucocorticoid barrier and suggests PDE4B-associated HSD11B2 regulation as a potential mechanistic target for FGR intervention.