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Glucocorticoids and Sex-Dependent Development of Brain Glucocorticoid and Mineralocorticoid Receptors

Departments of Physiology (D.O., S.G.M.), Obstetrics and Gynecology (S.G.M.), and Medicine (S.G.M.), Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Dr. S. G. Matthews, Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: stephen.matthews{at}utoronto.ca

We have previously shown that repeated antenatal synthetic glucocorticoid exposure has sex-specific effects on hypothalamic-pituitary-adrenal development in the fetal and adult guinea pig. However, little is known about the mechanisms that underlie these sex-specific outcomes. In the current study we demonstrated that glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) exhibit sex differences in their temporal and spatial expression during fetal and early postnatal life. During development, we observed decreased GR mRNA in the paraventricular nucleus, decreased MR mRNA and MR protein in the hippocampus, and increased GR mRNA and GR protein in the hippocampus. We have also shown that on gestational d 50, maternally administered betamethasone (BETA) reduces fetal plasma ACTH and cortisol concentrations. BETA significantly affected hippocampal MR protein expression, and this effect was greatest in males. BETA was unable to autoregulate GR protein during fetal life, indicating that regulation of brain corticosteroid receptors is fundamentally different in fetal compared with adult life. The sex differences in the pattern of GR and MR expression during development may indicate different windows of vulnerability to prenatal glucocorticoid exposure in fetal life.

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