The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep
Restricted accessResearch articleFirst published online March, 2012
The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep
We determined the effects of prenatal dexamethasone administration in early gestation on development of the hypothalamic–pituitary–adrenal (HPA) axis up to 7 months of postnatal age with measurements of hormone levels and gene expression. Plasma adrenocorticotropic hormone and cortisol levels after corticotropin-releasing hormone (CRH)/arginine vasopressin challenge were lower in treatment females than in control females and treatment males. Calculation of cortisol to adrenocorticotropic hormone ratios indicated however that the adrenals of treatment females were more responsive to adrenocorticotropic hormone than control females or treatment males. Effects of treatment and sex dependence at 7 months of age were observed in levels of hypothalamic CRH messenger RNA (mRNA), hypothalamic arginine vasopressin mRNA, pituitary proopiomelanocortin mRNA, pituitary prohormone convertase 1 and prohormone convertase 2, glucocorticoid receptor and mineralocorticoid receptor in the hypothalamus and hippocampus, adrenal adrenocorticotropic hormone receptor, steroidogenic acute regulatory, 3β hydroxysteroid dehydrogenase, and 11β hydroxysteroid dehydrogenase type 2 mRNA. The results indicate that exposure to glucocorticoids in early pregnancy produces persisting and sex-dependent effects on the hypothalamic–pituitary–adrenal axis at 7 months of age.
ChallisJRGMatthewsSGGibbWLyeSJ. Endocrine and paracrine regulation of birth at term and preterm 1. Endocr Rev. 2000;21(5):514–550.
2.
IkegamiMJobeAHNewnhamJPolkDHWilletKESlyP. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med. 1997;156(1):178–184.
3.
DunlopSAArcherMAQuinlivanJABeazleyLDNewnhamJP. Repeated prenatal corticosteroids delay myelination in the ovine central nervous system. J Matern Fetal Med. 1997;6(6):309–313.
4.
SlobodaDMNewnhamJP. Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term. J Endocrinol. 2000;165(1):79–91.
5.
ChallisJRGSlobodaDMatthewsSGThe fetal placental hypothalamic–pituitary–adrenal (HPA) axis, parturition and post natal health. Mol Cell Endocrinol. 2001;185(1-2):135–144.
6.
SlobodaDMMossTJGurrinLCNewnhamJP. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J Endocrinol. 2002;172(1):71–81.
SlobodaDMMossTJMLiSHepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab. 2005;289(4):721–728.
9.
SlobodaDMMossTJMLiSPrenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007;292(1):E61–E70.
10.
BraunTLiSMossTJMMaternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. J Endocrinol. 2007;194(2):337–347.
11.
SlobodaDMMossTJMLiSMatthewsSGChallisJRGNewnhamJP. Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11 {beta}-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure. J Endocrinol. 2008;197(2):213–220.
12.
DavidMForestMG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr. 1984;105(5):799–803.
13.
PangSYPollackMSMarshallRNImmkenL. Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med. 1990;322(2):111–115.
14.
DorrHGSippellWG. Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels. J Clin Endocrinol Metab. 1993;76(1):117–120.
15.
HirvikoskiTNordenströmALindholmT Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. Obstet Gynecol Surv2007;62:382–384.
16.
DodicMAbouantounTO’ConnorAWintourEMMoritzKM. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension. 2002;40(5):729–734.
17.
MoritzKButkusAHantzisVPeersAWintourEMDodicM. Prolonged low-dose dexamethasone, in early gestation, has no long-term deleterious effect on normal ovine fetuses. Endocrinology. 2002;143(4):1159–1165.
18.
DodicMHantzisVDuncanJProgramming effects of short prenatal exposure to cortisol. FASEB J. 2002;16(9):1017–1026.
19.
DodicMMcAlindenATJefferiesAJDifferential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep. J Physiol. 2006;571(pt 3):651–660.
20.
HantzisVAlbistonAMatsacosDEffect of early glucocorticoid treatment on MR and GR in late gestation ovine kidney. Kidney Int. 2002;61(2):405–413.
21.
DodicMPeersAMoritzKHantzisVWintourEM. No evidence for HPA reset in adult sheep with high blood pressure due to short prenatal exposure to dexamethasone. Am J Physiol Regul Integr Comp Physiol2002;282(2):R343–R350.
22.
De BlasioMJDodicMJefferiesAJMaternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. Am J Physiol Endocrinol Metab. 2007;293(1):E75–E82.
23.
RoghairRDLambFSMillerFJScholzTDSegarJL. Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity. Am J Physiol Regul Integr Comp Physiol2005;288(1):46–53.
24.
RoghairRDSegarJLSharmaRVNewborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension. Am J Physiol Regul Integr Comp Physiol2005;289(4):R1169–R1176.
25.
LimGBJeyaseelanKWintourEM. Ontogeny of erythropoietin gene expression in the sheep fetus: effect of dexamethasone at 60 days of gestation. Blood. 1994;84(2):460–466.
26.
GlickmanJAChallisJR. The changing response pattern of sheep fetal adrenal cells throughout the course of gestation. Endocrinology. 1980;106(5):1371–1376.
27.
BraunTLiSSlobodaDMEffects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. Endocrinology. 2009;150(12):5466–5477.
28.
MossTJMSlobodaDMGurrinLCProgramming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Compar Physiol. 2001;281(3):960–970.
29.
MossTJMDohertyDANitsosISlobodaDMHardingRNewnhamJP. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol. 2005;192(1):146–152.
30.
JaquieryALOliverMHBloomfieldFH. Fetal exposure to excess glucocorticoid is unlikely to explain the effects of periconceptional undernutrition in sheep. J Physiol. 2006;572(pt 1):109–118.
31.
BallardPLKittermanJABlandRDOntogeny and regulation of corticosteroid binding globulin capacity in plasma of fetal and newborn lambs. Endocrinology. 1982;110(2):359–366.
32.
ChallisJRNancekievillEALyeSJ. Possible role of cortisol in the stimulation of cortisol-binding capacity in the plasma of fetal sheep. Endocrinology. 1985;116(3):1139–1144.
33.
PhillipsDIWBarkerDJPFallCHDElevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?J Clin Endocrinol Metab. 1998;83(3):757–760.
34.
MatthewsSGHeavensRPSirinathsingjiDJS. Cellular localization of corticotropin releasing factor mRNA in the ovine brain. Brain Res Mol Brain Res. 1991;11(2):171–176.
35.
MatthewsSGChallisJR. Regulation of CRH and AVP mRNA in the developing ovine hypothalamus: effects of stress and glucocorticoids. Am J Physiol. 1995;268(6 pt 1):1096–1107.
36.
YangKHammondGLChallisJR. Characterization of an ovine glucocorticoid receptor cDNA and developmental changes in its mRNA levels in the fetal sheep hypothalamus, pituitary gland and adrenal. J Mol Endocrinol1992;8(2):173–180.
37.
MatthewsSGHanXLuFChallisJR. Developmental changes in the distribution of pro-opiomelanocortin and prolactin mRNA in the pituitary of the ovine fetus and lamb. J Mol Endocrinol. 1994;13(2):175–185.
38.
DaiGSmeekensSPSteinerDFMcMurtryJPKwokSCM. Characterization of multiple prohormone convertase PC1/3 transcripts in porcine ovary. Biochim Biophys Acta. 1995;1264(1):1–6.
39.
SeidahNGFournierHBoileauGBenjannetSRondeauNChretienM. The cDNA structure of the porcine pro-hormone convertase PC 2 and the comparative processing by PC 1 and PC 2 of the N-terminal glycopeptide segment of porcine POMC. FEBS Lett. 1992;310(3):235–239.
40.
ZhaoHFSimardJLabrieCBretonNRheaumeE. Molecular cloning, cDNA structure and predicted amino acid sequence of bovine 3 beta-hydroxy-5-ene steroid dehydrogenase/delta 5-delta 4 isomerase. FEBS Lett. 1989;259(1):153–157.
41.
Van HarmelenVAriapartPHoffstedtJLundkvistIBringmanSArnerP. Increased adipose angiotensinogen gene expression in human obesity. Obes Res. 2000;8(4):337–341.
42.
GyomorySGuptaSLyeSJGibbWLabrieFChallisJRG. Temporal expression of prostaglandin H synthase type 2 (PGHS-2) and P45OC17 in ovine placentomes with the natural onset of labour. Placenta. 2000;21(5-6):478–486.
43.
BradfordMM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.
44.
RitzénEM. Prenatal dexamethasone treatment of fetuses at risk for congenital adrenal hyperplasia: benefits and concerns. Semin Neonatol. 2001;6(4):357–362.
45.
NewnhamJPMossTJ. Antenatal glucocorticoids and growth: single versus multiple doses in animal and human studies. Semin Neonatol. 2001;6(4):285–292.
46.
MossTJHardingRNewnhamJP. Lung function, arterial pressure and growth in sheep during early postnatal life following single and repeated prenatal corticosteroid treatments. Early Hum Dev. 2002;66(1):11–24.
47.
CurrieISBrooksAN. Corticotrophin-releasing factors in the hypothalamus of the developing fetal sheep. J Dev Physiol. 1992;17(5):241–246.
48.
PradierPTournaireCDalleMDelostP. Plasma concentrations of adrenocorticotropin-related peptides in lambs injected with ovine corticotropin releasing factor or vasopressin. J Dev Physiol. 1989;11(2):103–109.
49.
LuFYangK. Regulation of ovine fetal pituitary function by corticotrophin-releasing hormone, arginine vasopressin and cortisol in vitro. J Endocrinol. 1994;143(1):199–208.
50.
AlmeidaOFCanoineVAliSHolsboerFPatchevVK. Activational effects of gonadal steroids on hypothalamo-pituitary-adrenal regulation in the rat disclosed by response to dexamethasone suppression. J Neuroendocrinol. 1997;9(2):129–134.
51.
WhittleWLPatelFAAlfaidyNGlucocorticoid regulation of human and ovine parturition: the relationship between fetal hypothalamic-pituitary-adrenal axis activation and intrauterine prostaglandin production. Biol Reprod. 2001;64(4):1019–1032.
52.
DongWSeidelBMarcinkiewiczMChretienMSeidahNGDayR. Cellular localization of the prohormone convertases in the hypothalamic paraventricular and supraoptic nuclei: selective regulation of PC1 in corticotrophin-releasing hormone parvocellular neurons mediated by glucocorticoids. J Neurosci. 1997;17(2):563–575.
53.
StevensABegumGCookAEpigenetic changes in the hypothalamic proopiomelanocortin and glucocorticoid receptor genes in the ovine fetus after periconceptional undernutrition. Endocrinology. 2010;151(8):3652–3664.
54.
ConnorKLChallisJRvan ZijlPDo alterations in placental 11beta-hydroxysteroid dehydrogenase (11betaHSD) activities explain differences in fetal hypothalamic-pituitary-adrenal (HPA) function following periconceptional undernutrition or twinning in sheep?Reprod Sci. 2009;16(12):1201–1212.
