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Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function.

ABSTRACT: 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(0)) 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.

SUBMITTER: Iqbal M

PROVIDER: S-EPMC3413075 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function.

Iqbal Majid M Moisiadis Vasilis G VG Kostaki Alisa A Matthews Stephen G SG

Endocrinology 20120507 7

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(0)) received betamethasone (BETA; 1 mg/kg) o ...[more]

PMID: 22564976

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Project description:Natural glucocorticoids, a class of cholesterol-derived hormones, modulate an array of metabolic, anti-inflammatory, immunosuppressive and cognitive signaling. The synthesis of natural glucocorticoids, largely cortisol in humans, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and exhibits pronounced circadian variation. Considering the central regulatory function of endogenous glucocorticoids, maintenance of the circadian activity of the HPA axis is essential to host survival and chronic disruption of such activity leads to systemic complications. There is a great deal of interest in synthetic glucocorticoids due to the immunosuppressive and anti-inflammatory properties and the development of novel dosing regimens that can minimize the disruption of endogenous activity, while still maintaining the pharmacological benefits of long-term synthetic glucocorticoid therapy. Synthetic glucocorticoids are associated with an increased risk of developing the pathological disorders related to chronic suppression of cortisol rhythmicity as a result of the potent negative feedback by synthetic glucocorticoids on the HPA axis precursors. In this study, a mathematical model was developed to explore the influence of chronopharmacological dosing of exogenous glucocorticoids on the endogenous cortisol rhythm considering intra-venous and oral dosing. Chronic daily dosing resulted in modification of the circadian rhythmicity of endogenous cortisol with the amplitude and acrophase of the altered rhythm dependent on the administration time. Simulations revealed that the circadian features of the endogenous cortisol rhythm can be preserved by proper timing of administration. The response following a single dose was not indicative of the response following long-term, repeated chronopharmacological dosing of synthetic glucocorticoids. Furthermore, simulations revealed the inductive influence of long-term treatment was only associated with low to moderate doses, while high doses generally led to suppression of endogenous activity regardless of the chronopharmacological dose. Finally, chronic daily dosing was found to alter the responsiveness of the HPA axis, such that a decrease in the amplitude of the cortisol rhythm resulted in a partial loss in the time-of-day dependent response to CRH stimulation, while an increase in the amplitude was associated with a more pronounced time-of-day dependence of the response.

Dataset Information

Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function.

Publications

Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function.

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