Prenatal corticosterone exposure programs sex-specific adrenal adaptations in mouse offspring

Abstract

Maternal stress can impair foetal development and program sex-specific disease outcomes in offspring through the actions of maternally produced glucocorticoids, predominantly corticosterone (Cort) in rodents. We have demonstrated in mice that male but not female offspring prenatally exposed to Cort (33 µg/kg/h for 60 h beginning at E12.5) develop cardiovascular/renal dysfunction at 12 months. At 6 months of age, renal function was normal but male offspring had increased plasma aldosterone concentrations, suggesting that altered adrenal function may precede disease. This study investigated the long-term impact of prenatal exposure to Cort on adrenal growth, morphology and steroidogenic capacity as well as plasma Cort concentrations in offspring at postnatal day 30 (PN30), 6 months and 12 months of age. Prenatal Cort exposure decreased adrenal volume, particularly of the zona fasciculata, in male offspring at PN30 but increased both relative and absolute adrenal weight at 6 months of age. By 12 months of age, male Cort-exposed offspring had reduced absolute adrenal weight in association with increased adrenal plaque deposition (lipogenic pigmentation). Plasma Cort concentrations were elevated in male 6-month offspring but not at other ages. mRNA expression of Mc2r (ACTH receptor) was increased in males at PN30, and Cyp11a1 expression was decreased at 6 and 12 months of age. There were no changes in the adrenals of female Cort-exposed offspring. This study demonstrates that prenatal Cort exposure induces offspring adrenal gland dysfunction in an age- and sex-specific manner, which may contribute to long-term programmed disease in male offspring after maternal stress.

Precocious glucocorticoid exposure reduces skeletal muscle satellite cells in the fetal rat

“…Gender differences were not studied. Although in a recent report no sex differences in birth weight were observed following a DEX infusion of 100 μg/(kg −1 •d −1 ) throughout gestation (Somm et al 2012), there is growing evidence for both humans and animal models that following exposure to an adverse intrauterine environment, some outcomes can be sex-specific (Aiken & Ozanne 2013; Cuffe et al 2017). Fiber morphometry measurements were made on the quadriceps muscle, whereas the MyHC isoform distribution and myogenin and MyoD measurements were determined on hind limb muscle homogenates.…”

Glucocorticoids and Reproduction: Traffic Control on the Road to Reproduction

“…Maternal exposure to dexamethasone in rats results in sexually dimorphic behavior in offspring, associated with structural changes to neuronal populations [43, 44]. In mice, the cardiovascular and renal renin-angiotensin-aldosterone systems also respond to elevated prenatal corticosterone in a sexually-dimorphic manner, potentially through altering adrenal function [45– 47]. Epigenetic factors may also play a key role in the glucocorticoid-driven effects of fetal programming, including altered methylation status of GR following neonatal dexamethasone exposure [48].…”

Placental O-GlcNAc-transferase expression and interactions with the glucocorticoid receptor are sex specific and regulated by maternal corticosterone exposure in mice

“…These adaptations were characterised by upregulation of the glucocorticoid barrier in females but dysregulated expression of growth and vasculogenic factors such as Igf2 and Vegfa together with structural alterations of the placenta at E17.5 in males only 4 . This was associated with impaired renal 28 , adrenal 29 and cardiovascular function 2 only in male offspring. While this suggests that sex differences in the level of fetal glucocorticoid exposure may be contributing to the sex specific disease outcomes, it is clear that placental adaptations mediate these sex differences.…”