Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation

Keller‐Wood, Maureen; Powers, Michael E.; Gersting, Jason A.; Ali, Nyima; Wood, Charles E.

doi:10.1152/physiolgenomics.00176.2005

Cited by 30 publications

(35 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…lessening the negative feedback influence of circulating or locally produced cortisol on the hippocampal regulation of HPA activity. Our data, together with previous reports (Andrews & Matthews 2000, Keller-Wood et al 2006, suggest that a reduction in late gestational hippocampal GR could facilitate a rise in fetal adrenocorticotropin (ACTH) and cortisol levels through a release of the hippocampal restraint on HPA activity. Here we further suggest that fetal hippocampal 11bHSD1 may regulate glucocorticoid accessibility to hippocampal GR (and MR) during fetal life by converting local inactive cortisone to bio-active cortisol.…”

Section: Hippocampal Gene Expression Ontogeny and Fetal Hpa Developmesupporting

confidence: 78%

“…This trend corresponds to a widely observed increase in hypothalamic-pituitary-adrenal (HPA) activity in late gestation, but presumably also requires a lessening of negative regulatory control of HPA activity. We have previously reported changes in gene expression in the fetal ovine hypothalamus and pituitary consistent with a late gestational maturation of these organs (Matthews & Challis 1996), but there is limited information on hippocampal gene expression ontogeny in the context of changes in negative regulatory control of HPA activity in late gestation in the fetal sheep (Keller-Wood et al 2006). Hippocampal corticosteroid receptors (both type 1 (mineralocorticoid receptor, MR) and type 2 (glucocorticoid receptor, GR)) and metabolizing enzymes (11b-hydroxysteroid dehydrogenases, 11bHSD) regulate glucocorticoid action, but their role in fetal HPA axis activation is unclear.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Sloboda¹,

Moss²,

Li³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

To determine the expression of glucocorticoid metabolizing and action genes in the hippocampus of fetal, neonatal, and adult sheep. Pregnant ewes (or their fetuses) received intramuscular injections of saline or betamethasone (BETA, 0-5 mg/kg) at 104, 111, 118, and/or 125 days of gestation (dG). Hippocampal tissue was collected prior to (75, 84, and 101 dG), during (109 and 116 dG), or after (121, 132, and 146 dG; 6 and 12 postnatal weeks; 3 . 5 years of age) saline or BETA injections. Hippocampal glucocorticoid receptor (GR), mineralocorticoid receptor (MR), and 11b-hydroxysteroid dehydrogenase (11bHSD)1 and 11bHSD2 mRNA levels were determined using qRT-PCR. Control animals late in gestation demonstrated a decrease in mRNA encoding GR and 11bHSD1, whereas 11bHSD2 was undetectable, consistent with a damping of the negative feedback influence of circulating or locally produced cortisol on the hypothalamic-pituitary-adrenal (HPA) axis. BETA-administration had transient effects on fetal GR and MR, and early in postnatal life (12 weeks of age) 11bHSD1 mRNA was increased. Hippocampal MR mRNA was elevated in adult offspring exposed to either one or four doses of maternal BETA (P!0 . 001). Four courses of maternal BETA increased 11bHSD2 (P!0 . 05) but not 11bHSD1 mRNA levels. Late in gestation a reduction in hippocampal GR and 11bHSD1 mRNA suggests lessening of glucocorticoid negative feedback, facilitating increased preterm HPA activity and parturition. Adult offspring of BETA-treated mothers demonstrated increased MR and 11bHSD2 mRNA, therefore it appears that exposure of fetus to high levels of synthetic glucocorticoids may have long-lasting effects on the hippocampal expression of HPA-related genes into adulthood.

show abstract

Section: Hippocampal Gene Expression Ontogeny and Fetal Hpa Developmesupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Sloboda¹,

Moss²,

Li³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Late gestation is characterized by marked changes in the concentrations of several steroid hormones, including glucocorticoids, estrogens, and androgens [2][3][4][5][6]. We have recently reported developmental changes in the expression of glucocorticoid and mineralocorticoid receptors in fetal brainstem, hypothalamus, and pituitary [7]. For example, decreases in the pituitary expression of the Address all correspondence to: Charles E. Wood, Ph.D., Box 100274, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610-0274.…”

Section: Introductionmentioning

confidence: 99%

Ontogeny of androgen receptor expression in the ovine fetal central nervous system and pituitary

Wood

Keller‐Wood

2008

Neuroscience Letters

Self Cite

View full text Add to dashboard Cite

In fetal sheep, circulating androgens influence fetal stress responsiveness and timing of parturition. Nevertheless, little is known about the presence and development of androgen receptors in the fetal brain. The present study was undertaken to test the hypothesis that expression of androgen receptor occurs in fetal brain and pituitary, and that the abundance of the AR is ontogenetically regulated. We isolated mRNA from pituitary, hypothalamus, hippocampus, and brainstem in fetal sheep that were 80, 100, 120, 130, 145 days gestation, and 1 and 7 days postnatal (n=4-5/group). Using real-time RT-PCR, we measured mRNA expression levels of the receptor in these brain regions and pituitary. In a separate study, we isolated protein from the same brain regions in fetal sheep that were 80 (n=3), 120 (n=4), and 145 (n=4) days. AR mRNA expression in hypothalamus increased in late gestation, starting at 145 days, and increasing progressively after birth. A trend of increasing AR protein in hypothalamus was not significant. AR mRNA expression in pituitary was elevated after 80 days gestation, but with no further increases or decreases in late gestation, while AR protein increased significantly at the end of gestation. In hippocampus and brainstem AR mRNA was constant throughout the latter half of gestation, and AR protein was below the sensitivity of our western blot assay. We conclude that the fetal brain and pituitary are target sites for circulating androgens or androgen precursors in fetal plasma, and we speculate that the increase in hypothalamic action of androgens immediately prior to birth might be integral to the timing of parturition. Keywordsreal-time PCR; sheep; parturition; neuroendocrinology; placenta; adrenal In fetal sheep, there are several notable developmental changes in the neuroendocrine control mechanisms that prepare the fetus for postnatal life. We and others have reported maturational changes in the neuroendocrine components of the fetal hypothalamus-pituitary-adrenal axis; the development of this endocrine axis is important for the development of appropriate fetal responses to stress as well as the control of parturition in this species [1]. Late gestation is characterized by marked changes in the concentrations of several steroid hormones, including glucocorticoids, estrogens, and androgens [2][3][4][5][6]. We have recently reported developmental changes in the expression of glucocorticoid and mineralocorticoid receptors in fetal brainstem, hypothalamus, and pituitary [7]. For example, decreases in the pituitary expression of the Address all correspondence to: Charles E. Wood, Ph.D., Box 100274, Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610-0274. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting pro...

show abstract

“…In sheep, both receptors are expressed within key regulatory areas of the HPA axis: the hypothalamus, hippocampus, brainstem, and pituitary (25,35,36). Activation of central and pituitary GR leads to feedback inhibition of stress-induced HPA axis activation, thereby reducing ACTH and cortisol secretion (24).…”

mentioning

confidence: 99%

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Lingis

Richards

Keller‐Wood

2011

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Lingis M, Richards EM, Keller-Wood M. Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes. Am J Physiol Endocrinol Metab 300: E592-E599, 2011. First published January 4, 2011; doi:10.1152/ajpendo.00560.2010.-During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus.cortisol; adrenocorticotropic hormone; pregnancy; canrenoate; aldosterone IN STUDIES OF BOTH WOMEN (8) and ewes (3), basal plasma adrenocorticotropic hormone (ACTH) and cortisol have been shown to increase during pregnancy. The increase in adrenal steroid secretion is critical for normal pregnancy. Reduction of either maternal cortisol or maternal aldosterone results in alterations in maternal and fetal physiology (19 -21). We have hypothesized that there is a change in the regulation of basal ACTH in the pregnant state. Previous studies in our laboratory in adrenalectomized sheep have shown that the concentration for cortisol replacement required to normalize basal plasma ACTH is increased in pregnancy and that replacement of pregnant ewes with cortisol to plasma concentrations similar to those measured in nonpregnant ewes increases both basal and hypotension-stimulated ACTH release (23,26). On the other hand, in studies using adrenal-intact ewes, the inhibition of ACTH produced by raising plasma cortisol above resting levels is not different during pregnancy (23). Therefore, we have hypothesized that during pregnancy the "set point" of the negative feedback regulation by cortisol is increased, and/or a greater increase in cortisol is required in the pregnant s...

show abstract

Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation

Cited by 30 publications

References 40 publications

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure

Ontogeny of androgen receptor expression in the ovine fetal central nervous system and pituitary

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Contact Info

Product

Resources

About