Dexamethasone induces fetal developmental toxicity through affecting the placental glucocorticoid barrier and depressing fetal adrenal function

This study evaluates the neuroendocrine-interference mechanism underlying dexamethasone-induced developmental toxicity. Pregnant mice were treated with various doses of dexamethasone (0, 0.5, 2.0 and 8.0 mg/kg), corticosterone levels in maternal serum, mRNA expressions of maternal and fetal adrenal steroidogenic acute regulatory protein (StAR), cytochrome P450 responsible for cholesterol side chain cleavage (P450scc) and placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) were measured. And the expressions of StAR and P450scc were also measured in cultured primary human fetal adrenocortical cells treated with various concentrations of dexamethasone (0, 1, 10 and 100 μmol/L) for 24 h. Mice suffered from intrauterine growth retardation (IUGR) after exposure to dexamethasone. The IUGR rate was augmented to 42.9% and 95.7% in 2.0 and 8.0 mg/kg dexamethasone groups, respectively (P < 0.01). The level of maternal serum corticosterone in three dexamethasone groups were decreased to 31.8%, 34.8% and 32.9%, respectively (P < 0.05 or P < 0.01), as compared with the control. Furthermore, the mRNA expressions of maternal and fetal adrenal StAR and P450scc in 8.0 mg/kg dexamethasone groups were decreased to 19.3% and 10.8%, 11.0% and 9.9% of that in the corresponding controls, respectively (P < 0.05). The mRNA expressions of placental 11β-HSD-2 were dose-dependently reduced in dexamethasone groups, particularly, the mRNA decreased to 22.2% in 8.0 mg/kg dexamethasone group, as compared with the control (P = 0.15). No obvious changes of StAR and P450scc in vitro after dexamethasone treatment. These suggest that prenatal dexamethasone exposure induces fetal developmental toxicity. A possible underlying mechanism is that dexamethasone may affect the placental glucocorticoid barrier and depressing fetal adrenal function.

► Prenatal dexamethasone exposure induces fetal developmental toxicity.
► Dexamethasone leads fetal overexposure to exogenous and maternal glucocorticoid.
► Dexamethasone has no direct effect on steroidogenesis of fetal adrenal.
► Dexamethasone suppresses fetal adrenal function by negative feedback of HPA axis.