Hostname: page-component-8448b6f56d-sxzjt Total loading time: 0 Render date: 2024-04-18T17:53:26.966Z Has data issue: false hasContentIssue false
  • English
  • Français

The impact of maternal synthetic glucocorticoid administration in late pregnancy on fetal and early neonatal hypothalamic–pituitary–adrenal axes regulatory genes is dependent upon dose and gestational age at exposure

Published online by Cambridge University Press:  25 September 2012

S. Li ,
T. J. M. Moss ,
I. Nitsos ,
S. G. Matthews ,
J. R. G. Challis ,
J. P. Newnham  and
D. M. Sloboda
S. Li*
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Women and Infants Research Foundation of Western Australia, Perth, Australia
T. J. M. Moss
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, VIC, Australia
I. Nitsos
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia The Ritchie Centre, Monash Institute of Medical Research and Department of Obstetrics and Gynaecology, Monash University, VIC, Australia
S. G. Matthews
Affiliation:
Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada
J. R. G. Challis
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Canada
J. P. Newnham
Affiliation:
School of Women's and Infants’ Health, The University of Western Australia, WA, Australia Women and Infants Research Foundation of Western Australia, Perth, Australia
D. M. Sloboda
Affiliation:
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Canada
*
Address for correspondence: S. Li, School of Women's and Infants’ Health, The University of Western Australia, M550, Crawley, WA 6009, Australia. Email Shaofu.li@uwa.edu.au
Get access Rights & Permissions [Opens in a new window]

Abstract

In this study, we determined the gene and/or protein expression of hypothalamic–pituitary–adrenal (HPA) axis regulatory molecules following synthetic glucocorticoid exposures. Pregnant sheep received intramuscular saline or betamethasone (BET) injections at 104 (BET-1), 104 and 111(BET-2) or 104, 111 and 118 (BET-3) days of gestation (dG). Samples were collected at numerous time-points between 75 dG and 12 weeks postnatal age. In the BET-3 treatment group, fetal plasma cortisol levels were lower at 145 dG than controls and gestational length was lengthened significantly. The cortisol:adrenocorticotropic hormone (ACTH) ratio in fetal plasma of control and BET-3 fetuses rose significantly between132 and 145 dG, and remained elevated in lambs at 6 and 12 weeks of age; this rise was truncated at day 145 in fetuses of BET-3 treated mothers. After BET treatment, fetal and postnatal pituitary proopiomelanocortin mRNA levels were reduced from 109 dG to 12 weeks postnatal age; pituitary prohormone convertase 1 and 2 mRNA levels were reduced at 145 dG and postnatally; hypothalamic arginine vasopressin mRNA levels were lowered at all time-points, but corticotrophin-releasing hormone mRNA levels were reduced only in postnatal lambs. Maternal BET increased late fetal and/or postnatal adrenal mRNA levels of ACTH receptor and 3β hydroxysteroid dehydrogenase but decreased steroidogenic acute regulatory protein and P450 17-α hydroxylase. The altered mRNA levels of key HPA axis regulatory proteins after maternal BET injections suggests processes that may subserve long-term changes in HPA activity in later life after prenatal exposure to synthetic glucocorticoids.

Keywords

adrenalfetusglucocorticoidhypothalamic–pituitary–adrenal axisprogramming
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 4 , Issue 1 , February 2013 , pp. 77 - 89
Copyright
Copyright © Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Polyakov, A, Cohen, S, Marita, B, et al. Patterns of antenatal corticosteroid prescribing 1998–2004. Aust N Z J Obstet Gynaecol. 2007; 47, 42–45.Google Scholar
2.Crowley, P. Prophylactic corticosteroids for preterm birth. Cochrane Database Syst Rev. 2000, CD000065.Google Scholar
3.Ikegami, M, Jobe, AH, Newnham, J, et al. Repetitive prenatal glucocorticoids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med. 1997; 156, 178–184.Google Scholar
4.Moss, TJ, Sloboda, DM, Gurrin, LC, et al. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Comp Physiol. 2001; 281, R960–R970.Google Scholar
5.Sloboda, DM, Newnham, JP, Challis, JR. Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term. J Endocrinol. 2000; 165, 79–91.Google Scholar
6.Sloboda, DM, Newnham, JP. Repeated maternal glucocorticoid administration and the developing liver in fetal sheep. J Endocrinol. 2002; 175, 535–543.CrossRefGoogle ScholarPubMed
7.Sloboda, DM, Challis, JR, Moss, TJ, Newnham, JP. Synthetic glucocorticoids: antenatal administration and long-term implications. Curr Pharm Des. 2005; 11, 1459–1472.Google Scholar
8.Newnham, JP. Is prenatal glucocorticoid administration another origin of adult disease? Clin Exp Pharmacol Physiol. 2001; 28, 957–961.Google Scholar
9.Sloboda, DM, Moss, TJ, Gurrin, LC, Newnham, JP, Challis, JR. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function. J Endocrinol. 2002; 172, 71–81.CrossRefGoogle ScholarPubMed
10.Sloboda, DM, Moss, TJ, Li, S, et al. Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep. Am J Physiol Endocrinol Metab. 2007; 292, E61–E70.Google Scholar
11.Benediktsson, R, Lindsay, RS, Noble, J, Seckl, JR, Edwards, CR. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet. 1993; 341, 339–341.Google Scholar
12.Cleasby, ME, Livingstone, DE, Nyirenda, MJ, Seckl, JR, Walker, BR. Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood? Eur J Endocrinol. 2003; 148, 129–138.Google Scholar
13.Owen, D, Matthews, SG. Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function in juvenile guinea pigs. J Neuroendocrinol. 2007; 19, 172–180.Google Scholar
14.Banjanin, S, Kapoor, A, Matthews, SG. Prenatal glucocorticoid exposure alters hypothalamic-pituitary-adrenal function and blood pressure in mature male guinea pigs. J Physiol. 2004; 558, 305–318.CrossRefGoogle ScholarPubMed
15.Fowden, AL, Li, J, Forhead, AJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance? Proc Nutr Soc. 1998; 57, 113–122.Google Scholar
16.McDonald, TJ. Hypothalamic glucocorticoid implants prevent fetal ovine adrenocorticotropin secretion in response to stress. Endocrinology. 1990; 127, 2862–2868.CrossRefGoogle ScholarPubMed
17.Akagi, K, Berdusco, ET, Challis, JR. Cortisol inhibits ACTH but not the AVP response to hypoxaemia in fetal lambs at days 123-128 of gestation. J Dev Physiol. 1990; 14, 319–324.Google Scholar
18.Moss, TJ, Harding, R, Newnham, JP. Lung function, arterial pressure and growth in sheep during early postnatal life following single and repeated prenatal corticosteroid treatments. Early Hum Dev. 2002; 66, 11–24.CrossRefGoogle ScholarPubMed
19.Jobe, AH, Moss, TJ, Nitsos, I, et al. Betamethasone for lung maturation: testing dose and formulation in fetal sheep. Am J Obstet Gynecol. 2007; 197:523 e521–526.CrossRefGoogle ScholarPubMed
20.Gatford, KL, Owens, JA, Li, S, et al. Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny. Am J Physiol Endocrinol Metab. 2008; 295, E170–E178.Google Scholar
21.Sloboda, DM, Moss, TJ, Li, S, et al. Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab. 2005; 289, E721–E728.CrossRefGoogle ScholarPubMed
22.Sloboda, DM, Moss, TJ, Li, S, et al. Expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase 1 and 2 in the fetal and postnatal ovine hippocampus: ontogeny and effects of prenatal glucocorticoid exposure. J Endocrinol. 2008; 197, 213–220.Google Scholar
23.Gutierrez-Adan, A, Cushwa, WT, Anderson, GB, Medrano, JF. Ovine-specific Y-chromosome RAPD-SCAR marker for embryo sexing. Anim Genet. 1997; 28, 135–138.Google Scholar
24.Holloway, AC, Howe, DC, Chan, G, et al. Urocortin: a mechanism for the sustained activation of the HPA axis in the late-gestation ovine fetus? Am J Physiol Endocrinol Metab. 2002; 283, E165–E171.Google Scholar
25.Zarkawi, M, Soukouti, A. Serum progesterone levels using radioimmunoassay during oestrous cycle of indigenous Damascus does. NZ J Agric Res. 2001; 44, 165–170.Google Scholar
26.Bloomfield, FH, Oliver, MH, Hawkins, P, et al. Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. Endocrinology. 2004; 145, 4278–4285.Google Scholar
27.McCabe, L, Marash, D, Li, A, Matthews, SG. Repeated antenatal glucocorticoid treatment decreases hypothalamic corticotropin releasing hormone mRNA but not corticosteroid Receptor mRNA expression in the fetal guinea-pig Brain. J Neuroendocrinol. 2001; 13, 425–431.Google Scholar
28.Zhao, HF, Simard, J, Labrie, C, Breton, N, Rheaume, E. 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, 153–157.Google Scholar
29.Dodic, M, Hantzis, V, Duncan, J, et al. Programming effects of short prenatal exposure to cortisol. In FASEB. 2002; 16, 1017–1026.CrossRefGoogle ScholarPubMed
30.Van Harmelen, V, Ariapart, P, Hoffstedt, J, et al. Increased adipose angiotensinogen gene expression in human obesity. In NAASO. 2000; 8, 337–341.Google Scholar
31.Jobe, AH, Wada, N, Berry, LM, Ikegami, M, Ervin, MG. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep. Am J Obstet Gynecol. 1998; 178, 880–885.Google Scholar
32.Moss, TJM, Doherty, DA, Nitsos, I, et al. Effects into adulthood of single or repeated antenatal corticosteroids in sheep. Am J Obstet Gynecol. 2005; 192, 146–152.Google Scholar
33.Matthews, SG, Challis, JR. CRH and AVP-induced changes in synthesis and release of ACTH from the ovine fetal pituitary in vitro: negative influences of cortisol. Endocrine. 1997; 6, 293–300.Google Scholar
34.Challis, JRG, Matthews, SG, Gibb, W, Lye, SJ. Endocrine and paracrine regulation of birth at term and preterm. Endocr Rev. 2000; 21, 514–550.Google Scholar
35.Levidiotis, ML, Wintour, EM, McKinley, MJ, Oldfield, BJ. Hypothalamic-hypophyseal vascular connections in the fetal sheep. Neuroendocrinology. 1989; 49, 47–50.Google Scholar
36.Berdusco, ET, Hammond, GL, Jacobs, RA, et al. Glucocorticoid-induced increase in plasma corticosteroid-binding globulin levels in fetal sheep is associated with increased biosynthesis and alterations in glycosylation. Endocrinology. 1993; 132, 2001–2008.Google Scholar
37.Berdusco, ET, Milne, WK, Challis, JR. Low-dose cortisol infusion increases plasma corticosteroid-binding globulin (CBG) and the amount of hepatic CBG mRNA in fetal sheep on day 100 of gestation. J Endocrinol. 1994; 140, 425–430.CrossRefGoogle ScholarPubMed
38.Clifton, VL. Sexually dimorphic effects of maternal asthma during pregnancy on placental glucocorticoid metabolism and fetal growth. Cell Tissue Res. 2005; 322, 63–71.CrossRefGoogle ScholarPubMed
39.Braun, T, Li, S, Sloboda, DM, et al. Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. Endocrinology. 2009; 150, 5466–5477.CrossRefGoogle ScholarPubMed
40.Ross, JT, McMillen, IC, Adams, MB, Coulter, CL. A premature increase in circulating cortisol suppresses expression of 11beta hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid in the adrenal of the fetal sheep. Biol Reprod. 2000; 62, 1297–1302.Google Scholar
41.MacLaughlin, SM, Walker, SK, Kleemann, DO, et al. Impact of periconceptional undernutrition on adrenal growth and adrenal insulin-like growth factor and steroidogenic enzyme expression in the sheep fetus during early pregnancy. Endocrinology. 2007; 148, 1911–1920.Google Scholar
42.Matthews, SG, Han, X, Lu, F, Challis, JR. 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, 175–185.Google Scholar
43.Matthews, SG, Owen, D, Banjanin, S, Andrews, MH. Glucocorticoids, hypothalamo-pituitary-adrenal (HPA) development, and life after birth. Endocr Res. 2002; 28, 709–718.Google Scholar
44.Matthews, SG, Challis, JR. Regulation of the hypothalamo-pituitary-adrenocortical axis in fetal sheep. Trends Endocrinol Metab. 1996; 7, 239–246.CrossRefGoogle ScholarPubMed
45.Seckl, JR, Cleasby, M, Nyirenda, MJ. Glucocorticoids, 11beta-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int. 2000; 57, 1412–1417.Google Scholar
46.Braun, T, Li, S, Moss, TJ, et al. Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. J Endocrinol. 2007; 194, 337–347.Google Scholar
47.Newnham, JP, Moss, TJM, Nitsos, I, Sloboda, DM. Antenatal corticosteroids: the good, the bad and the unknown. Curr Opin Obstet Gynecol. 2002; 14, 607–612.Google Scholar
48.Matthews, SG, Challis, JR. Regulation of CRH and AVP mRNA in the developing ovine hypothalamus: effects of stress and glucocorticoids. Am J Physiol. 1995; 268, E1096–E1107.Google ScholarPubMed
49.Bloomfield, FH, Oliver, MH, Hawkins, P, et al. A periconceptional nutritional origin for noninfectious preterm birth. Science. 2003; 300, 606.Google Scholar
50.Matthews, SG, Yang, K, Challis, JR. Changes in glucocorticoid receptor mRNA in the developing ovine pituitary and the effects of exogenous cortisol. J Endocrinol. 1995; 144, 483–490.Google Scholar
51.Jones, CT, Roebuck, MM. ACTH peptides and the development of the fetal adrenal. J Steroid Biochem. 1980; 12, 77–82.Google Scholar
52.Rousseau, K, Kauser, S, Pritchard, LE, et al. Proopiomelanocortin (POMC), the ACTH/melanocortin precursor, is secreted by human epidermal keratinocytes and melanocytes and stimulates melanogenesis. FASEB J. 2007; 21, 1844–1856.Google Scholar
53.Rainey, WE, Carr, BR, Wang, ZN, Parker, CR Jr. Gene profiling of human fetal and adult adrenals. J Endocrinol. 2001; 171, 209–215.Google Scholar
54.Mansfield, CW, Carr, BR, Faye-Petersen, OM, et al. Differential gene expression in the adrenals of normal and anencephalic fetuses and studies focused on the Fras-1-related extracellular matrix protein (FREM2) gene. Reprod Sci. 2011; 18, 1146–1153.Google Scholar
55.Moritz, K, Butkus, A, Hantzis, V, et al. Prolonged low-dose dexamethasone, in early gestation, has no long-term deleterious effect on normal ovine fetuses. Endocrinology. 2002; 143, 1159–1165.Google Scholar