Transgenerational Effects of Prenatal Synthetic Glucocorticoids on Hypothalamic-Pituitary-Adrenal Function

Approximately 10% of pregnant women are at risk of preterm delivery and receive synthetic glucocorticoids (sGC) to promote fetal lung development. Studies have indicated that prenatal sGC therapy modifies hypothalamic-pituitary-adrenal (HPA) function in first-generation (F-1) offspring. The objective of this study was to determine whether differences in HPA function and behavior are evident in the subsequent (F-2) generation. Pregnant guinea pigs (F-o) received betamethasone (BETA; 1 mg/kg) or saline on gestational d 40/41, 50/51, and 60/61. F-1 females were mated with control males to create F-2 offspring. HPA function was assessed in juvenile and adult F-2 offspring. Locomotor activity was assessed in juvenile offspring. Analysis of HPA-related gene expression was undertaken in adult hippocampi, hypothalami, and pituitaries. Locomotor activity was reduced in F-2 BETA males (P < 0.05). F-2 BETA offspring displayed blunted cortisol response to swim stress (P < 0.05). After dexamethasone challenge, F-2 BETA males and females displayed increased and decreased negative feedback, respectively. F-2 BETA females had reduced pituitary levels of proopiomelanocortin (and adrenocorticotropic hormone), and corticotropin-releasing hormone receptor mRNA and protein (P < 0.05). F-2 BETA males displayed increased hippocampal glucocorticoid receptor (P < 0.001), whereas in BETA females, hippocampal glucocorticoid receptor and mineralocorticoid receptor mRNA were decreased (P < 0.05). In conclusion, prenatal BETA treatment affects HPA function and behavior in F-2 offspring. In F-2 BETA females, pituitary function appears to be primarily affected, whereas hippocampal glucocorticoid feedback systems appear altered in both F-2 BETA males and females. These data have clinical implication given the widespread use of repeat course glucocorticoid therapy in the management of preterm labour. (Endocrinology 153: 3295-3307, 2012)