Inhibition of placental 11β-HSD2 expression through cAMP/PKA signaling pathway induces intrauterine growth retardation.

It is known that excessive exposure to maternal glucocorticoids during fetal development can cause fetal intrauterine growth retardation (IUGR) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) plays an important role in the regulation of fetal glucocorticoid level. Our previous study has found that prenatal caffeine exposure (PCE) can inhibit placental 11β-HSD2 expression. However, the epigenetic mechanism and the role of 11β-HSD2 in PCE-induced IUGR remain undetermined. Pregnant Wistar rats were intragastrically administered caffeine (30 and 120 mg/kg·d) on gestational days 9-20. We found that caffeine decreased the fetal body weights, increased maternal/fetal serum and placental corticosterone levels; moreover, it increased placental early growth response factor 1 (EGR1) expression and decreased 11β-HSD2 expression. Further, in HTR-8/SVneo cells, caffeine inhibited the cAMP/PKA signal pathway, increased EGR1 expression, decreased 11β-HSD2 expression, and changed histone modifications (H3K9ac decrease, H3K9me2 increase) in the HSD11B2 promoter region. Adenylyl cyclase agonist and EGR1 knockdown all reversed the inhibition of 11β-HSD2 expression by caffeine. It is suggested that the cAMP/PKA/EGR1 signaling pathway mediates caffeine-induced 11β-HSD2 expression inhibition in placental trophoblasts. Finally, using clinical specimens, we confirmed the inhibition of cAMP/PKA signaling pathway, the increase of EGR1/SP1 expression ratio, and the decrease of 11β-HSD2 expression in IUGR placentas. Among them, 11β-HSD2 expression and neonatal birth weight were positively correlated with placental cAMP/PKA signaling pathway, but negatively correlated with EGR1/SP1 expression ratio. In conclusion, the cAMP/PKA signaling pathway and its regulated EGR1/SP1 expression ratio are common regulatory mechanisms of placental 11β-HSD2 in IUGR fetuses. This study elucidates the epigenetic mechanism of PCE on placental 11β-HSD2 expression. Combined with clinical verification, the common mechanism of placental 11β-HSD2 expression down-regulation and IUGR occurrence was proposed, which provided a new idea for exploring early warning and prevention targets of IUGR.