Abstract
Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery to reduce respiratory distress syndrome in the newborn. The prefrontal cortex (PFC) is important in regulating stress responses and related behaviours and expresses high levels of glucocorticoid receptors (GR). Further, antenatal exposure to sGC results in a hyperactive phenotype in first generation (F1) juvenile male and female offspring, as well as F2 and F3 juvenile females from the paternal lineage. We hypothesized that multiple courses of antenatal sGC modify gene expression in the PFC, that these effects are sex-specific and maintained across multiple generations, and that the gene sets affected relate to modified locomotor activity. We performed RNA sequencing on PFC of F1 juvenile males and females, as well as F2 and F3 juvenile females from the paternal lineage and used regression modelling to relate gene expression and behavior. Antenatal sGC resulted in sex-specific and generation-specific changes in gene expression. Further, the expression of 4 genes (C9orf116, Calb1, Glra3, and Gpr52) explained 20–29% of the observed variability in locomotor activity. Antenatal exposure to sGC profoundly influences the developing PFC; effects are evident across multiple generations and may drive altered behavioural phenotypes.
Highlights
Antenatal synthetic glucocorticoids are administered to women at risk for preterm delivery to decrease the morbidity and mortality in the newborn associated with preterm birth[8,9,10]
Antenatal exposure to Synthetic glucocorticoids (sGC) resulted in changes to gene expression in the prefrontal cortex (PFC) that persist across three generations of juvenile female offspring derived through the paternal lineage
Antenatal exposure to sGC resulted in a pattern of gene expression in the PFC consistent with reduced GABAergic signaling in F1-F3 offspring
Summary
Pregnant guinea pigs received 3 courses of the sGC betamethasone (sGC; 1 mg/kg) or saline control in late gestation, as previously described[18]. The dose of sGC used is comparable to that administered to pregnant women at risk of preterm delivery (~0.25 mg/kg) as the glucocorticoid receptor (GR) in guinea pigs has a 4-fold lower affinity for sGC42. Total locomotor activity in the open-field test (open-field activity; OFA) was measured in female and male offspring on postnatal day 19, and brains were collected at day 40, as previously reported[18]. The locomotor activity in the open-field, of the animals used for molecular analysis in the present study, was presented previously[18]. One animal of each sex from each litter was used in the molecular analysis of female offspring.
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