Repeated antenatal glucocorticoid treatment decreases hypothalamic corticotropin releasing hormone mRNA but not corticosteroid receptor mRNA expression in the fetal guinea-pig brain.
Approximately 10% of pregnant women are treated with synthetic glucocorticoids in late gestation, to promote fetal lung maturation. The effectiveness of this treatment has led to the use of repeated dose regimens, with little knowledge of the impact on neuroendocrine development. Animal studies have recently shown that repeated fetal glucocorticoid exposure can lead to permanent changes in hypothalamic-pituitary-adrenal (HPA) function in offspring. In this study, we hypothesized that such treatment modifies corticotropin releasing hormone (CRH), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) systems in the developing limbic system and hypothalamus. Pregnant guinea-pigs were treated with dexamethasone, betamethasone or vehicle on days 40,41,50,51,60 and 61 of gestation (birth = 68 days). On day 62, guinea-pigs were killed and the fetuses rapidly removed. Glucocorticoid treatment resulted in a dose-dependent reduction in plasma cortisol concentrations in both male and female fetuses. There was also a significant reduction in CRH mRNA expression in the hypothalamic paraventricular nucleus. In contrast, exposure to glucocorticoid increased MR mRNA expression in the hippocampus (CA1/2 and CA3) and dentate gyrus of female fetuses. There was a small but significant increase in GR mRNA expression in limbic structures in male fetuses following treatment with 1 mg/kg dexamethasone. However, there was no significant effect of glucocorticoid exposure on hippocampal GR mRNA expression in female fetuses, or hypothalamic GR mRNA in either males or females. In conclusion, repeated maternal glucocorticoid treatment inhibits fetal HPA function. The fact that CRH mRNA levels were reduced indicates that synthetic glucocorticoids enter the fetal brain. By contrast, fetal glucocorticoid exposure does not downregulate GR mRNA, and increases MR mRNA expression. The latter likely reflects removal of circulating endogenous ligand (cortisol). These alterations may form the basis for permanently modified HPA activity in later life.
McCabe
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Department of Physiology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Marash
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D
Li
A
A
Matthews
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SG
D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006168:Guinea Pigs; D007030:Hypothalamo-Hypophyseal System / Q000196:embryology / Q000502:physiology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000196:embryology / Q000502:physiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics*
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone