Glucocorticoid-induced fetal brain growth restriction is associated with p73 gene activation

Fetal exposure to excessive amounts of glucocorticoids (GCs) hampers proper brain development. The molecular mechanism(s) underlying these GCs effects are not well understood. We explored the impact of fetal exposure to maternal GCs on fetal brain expression of p63 and p73 transactivation (TA) and dominant negative (ΔN) gene variants that promote neural cell death (TA) and cell survival programs (ΔN). The fetoplacental enzyme 11β-hydroxysteroid dehydrogenase 2, which shields fetuses from maternal glucocorticoids, was inhibited throughout pregnancy by daily injection of carbenoxolone to pregnant dams. The expression of p63 and p73 gene variants and proteins was monitored by real-time rtPCR and Western blot in the brains of male and female fetuses. Carbenoxolone administration led to an overall enhanced level of corticosterone in the amniotic fluid of both male and female fetuses at late pregnancy. These enhanced corticosterone levels were associated with a significant reduction in fetal brain weights and a significant increase in TAp73 mRNA and p73 protein levels. However, the expression levels of TAp63 mRNA and p63 proteins were either suppressed or unaffected. The pro-neural survival gene variant ΔNp73 was significantly reduced in female and enhanced in male fetal brains, whereas ΔNp63 was significantly reduced in the brains of both genders. These data suggest that the GCs-induced negative impact on fetal brain development likely is due, at least in part, to their action of the pro-neural cell death gene variant TAp73 and to the modulation of the pro-survival ΔNp63 and ΔNp73 gene variants in a gender-dependent fashion.