The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal guinea pig model of growth restriction

ABSTRACT There are ongoing concerns that antenatal corticosteroids, which are administered to women at high risk of delivering preterm to reduce the incidence of respiratory distress syndrome, have adverse effects on fetal brain development and subsequent effects on behaviour and learning, when administered as repeated courses. The objective of this study was to examine if repeated betamethasone treatment alters the expression of the key-rate limiting enzyme, 5alpha-reductase, in the synthetic pathway of the potent neuroactive steroid allopregnanolone in the brain and placenta and if this effect is potentiated in growth restricted fetuses. To investigate this, pregnant guinea pigs carrying either control (sham surgery) or growth-restricted fetuses were treated with vehicle or betamethasone (1mg/kg/day) for 4 days prior to sacrifice (65d). Placental insufficiency was induced by the ablation of uterine artery branches supplying each placenta at mid gestation, resulting in fetal growth restriction characterised by brain sparing . Real time RT-PCR was used to determine relative 5alpha-reductase type 1 and 2 mRNA expression in the placenta and brain. Immunohistochemistry was used to examine the GFAP expression in the subcortical white matter, CA1 and dentate regions of the hippocampus. 5alpha-reductase type 2 mRNA expression in the brain was markedly reduced by betamethasone treatment in male fetuses compared to vehicle treated controls but not in female fetuses. In addition, 5alpha-reductase type 1 expression in the brain was increased by growth restriction and/or betamethasone treatment in female fetuses but expression in males fetuses did not increase. 5alpha-reductase type 2 expression in the placenta was markedly reduced by betamethasone treatment compared to vehicle treated control. IUGR and betamethasone treatment reduced GFAP expression in the CA1 region of the hippocampus in the brains of male but not female fetuses. These data indicate that betamethasone...