Cell and Tissue Research

, Volume 322, Issue 1, pp 81–88 | Cite as

Glucocorticoid programming of adult disease

  • Karen M. Moritz
  • Wee Ming Boon
  • E. Marelyn Wintour
Review

Abstract

Fetal exposure to elevated levels of glucocorticoids can occur naturally when maternal glucocorticoids are elevated in times of stress or when exogenous glucocorticoids are administered. Epidemiological studies and animal models have shown that, whereas short-term benefits may be associated with fetal glucocorticoid exposure, long-term deleterious effects may arise. This review compares the effects of exposure to natural versus synthetic glucocorticoids and considers the ways in which the timing of the exposure and the sex of the fetus may influence outcomes. Some of the long-term effects of glucocorticoid exposure may be explained by epigenetic mechanisms.

Keywords

Glucocorticoids (synthetic/natural) Fetal exposure Fetal sex Short-term benefits Long-term problems Epigenetic mechanisms Disease 

References

  1. Alfaidy N, Gupta S, DeMarco C, Caniggia I, Challis JR (2002) Oxygen regulation of placental 11 beta-hydroxysteroid dehydrogenase 2: physiological and pathological implications. J Clin Endocrinol Metab 87:4797–4805CrossRefPubMedGoogle Scholar
  2. Andrews MH, Kostaki A, Setiawan E, McCabe L, Matthews SG (2004) Developmental regulation of 5-HT1A receptor mRNA in the fetal limbic system: response to antenatal glucocorticoid. Brain Res Dev Brain Res 149:39–44CrossRefPubMedGoogle Scholar
  3. Ausio J, Levin DB, De Amorim GV, Bakker S, Macleod PM (2003) Syndromes of disordered chromatin remodeling. Clin Genet 64:83–95CrossRefPubMedGoogle Scholar
  4. Banjanin S, Kapoor A, Matthews SG (2004) Prenatal glucocorticoid exposure alters hypothalamic–pituitary–adrenal function and blood pressure in mature male guinea pigs. J Physiol (Lond) 558:305–318CrossRefGoogle Scholar
  5. Barbazanges A, Piazza PV, Le Moal M, Maccari S (1996) Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci 16:3943–3949PubMedGoogle Scholar
  6. Bauer B, Hartz AM, Fricker G, Miller DS (2004) Pregnane X receptor up-regulation of P–glycoprotein expression and transport function at the blood-brain barrier. Mol Pharmacol 66:413–419PubMedGoogle Scholar
  7. Bispham J, Gopalakrishnan GS, Dandrea J, Wilson V, Budge H, Keisler DH, Broughton Pipkin F, Stephenson T, Symonds ME (2003) Maternal endocrine adaptation throughout pregnancy to nutritional manipulation: consequences for maternal plasma leptin and cortisol and the programming of fetal adipose tissue development. Endocrinology 144:3575–3585CrossRefPubMedGoogle Scholar
  8. Bloomfield FH, Oliver MH, Hawkins P, Campbell M, Phillips DJ, Gluckman PD, Challis JR, Harding JE (2003) A periconceptional nutritional origin for noninfectious preterm birth. Science 300:606CrossRefPubMedGoogle Scholar
  9. Bloomfield FH, Oliver MH, Hawkins P, Holloway AC, Campbell M, Gluckman PD, Harding JE, Challis JR (2004) Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic–pituitary–adrenal axis in late gestation. Endocrinology 145:4278–4285CrossRefPubMedGoogle Scholar
  10. Bourc’his D, Bestor TH (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431:96–99CrossRefPubMedGoogle Scholar
  11. Celsi G, Kistner A, Aizman R, Eklof AC, Ceccatelli S, Santiago A de, Jacobson SH (1998) Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring. Pediatr Res 44:317–322PubMedGoogle Scholar
  12. Clifton VL, Murphy VE (2004) Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta 25 (Suppl A):S45–S52CrossRefPubMedGoogle Scholar
  13. Dodic M, May CN, Wintour EM, Coghlan JP (1998) An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci (Lond) 94:149–155Google Scholar
  14. Dodic M, Peers A, Coghlan JP, May CN, Lumbers E, Yu Z, Wintour EM (1999) Altered cardiovascular haemodynamics and baroreceptor-heart rate reflex in adult sheep after prenatal exposure to dexamethasone. Clin Sci (Lond) 97:103–109Google Scholar
  15. Dodic M, Abouantoun T, O’Connor A, Wintour EM, Moritz KM (2002a) Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension 40:729–734CrossRefPubMedGoogle Scholar
  16. Dodic M, Hantzis V, Duncan J, Rees S, Koukoulas I, Johnson K, Wintour EM, Moritz K (2002b) Programming effects of short prenatal exposure to cortisol. FASEB J 16:1017–1026CrossRefPubMedGoogle Scholar
  17. Dodic M, Moritz K, Wintour EM (2003) Prenatal exposure to glucocorticoids and adult disease.Arch Physiol Biochem 111:61-69CrossRefPubMedGoogle Scholar
  18. Drake AJ, Walker BR, Seckl JR (2004) Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol 288:R34-R38Google Scholar
  19. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463CrossRefPubMedGoogle Scholar
  20. Figueroa JP, Acuna G, Rose JC, Massmann GA (2004) Maternal antenatal steroid administration at 0.55 gestation increases arterial blood pressure in young adult sheep offspring. J Soc Gynecol Invest (Suppl) 11:358AGoogle Scholar
  21. Fowden AL, Forhead AJ (2004) Endocrine mechanisms of intrauterine programming. Reproduction 127:515–526CrossRefPubMedGoogle Scholar
  22. Fujisawa Y, Nakagawa Y, Ren-Shan L, Ohzeki T (2004) Streptozotocin-induced diabetes in the pregnant rat reduces 11 beta-hydroxysteroid dehydrogenase type 2 expression in placenta and fetal kidney. Life Sci 75:2797–2805PubMedGoogle Scholar
  23. Goldstone AP (2004) Prader–Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 15:12–20PubMedGoogle Scholar
  24. Gomez Sanchez EP (1991) What is the role of the central nervous system in mineralocorticoid hypertension? Am J Hypertens 4:374–381PubMedGoogle Scholar
  25. Hantzis V, Albiston A, Matsacos D, Wintour EM, Peers A, Koukoulas I, Myles K, Moritz K, Dodic M (2002) Effect of early glucocorticoid treatment on MR and GR in late gestation ovine kidney. Kidney Int 61:405–413PubMedGoogle Scholar
  26. Hassig CA, Schreiber SL (1997) Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. Curr Opin Chem Biol 1:300–308CrossRefPubMedGoogle Scholar
  27. Henikoff S, Furuyama T, Ahmad K (2004) Histone variants, nucleosome assembly and epigenetic inheritance. Trends Genet 20:320–326CrossRefPubMedGoogle Scholar
  28. Huang BS, Wang H, Leenen FH (2005) Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats.Am J Physiol 288:H517-H524Google Scholar
  29. Jobe AH, Newnham JP, Moss TJ, Ikegami M (2003) Differential effects of maternal betamethasone and cortisol on lung maturation and growth in fetal sheep. Am J Obstet Gynecol 188:22–28CrossRefPubMedGoogle Scholar
  30. Jobe AH, Soll RF (2004) Choice and dose of corticosteroid for antenatal treatments. Am J Obstet Gynecol 190:878–881CrossRefPubMedGoogle Scholar
  31. John RM, Surani MA (2000) Genomic imprinting, mammalian evolution, and the mystery of egg-laying mammals. Cell 101:585–588CrossRefPubMedGoogle Scholar
  32. Kajantie E, Dunkel L, Turpeinen U, Stenman UH, Wood PJ, Nuutila M, Andersson S (2003) Placental 11 beta-hydroxysteroid dehydrogenase-2 and fetal cortisol/cortisone shuttle in small preterm infants. J Clin Endocrinol Metab 88:493–500PubMedGoogle Scholar
  33. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57:808–811PubMedGoogle Scholar
  34. Kanitz E, Otten W, Tuchscherer M, Manteuffel G (2003) Effects of prenatal stress on corticosteroid receptors and monoamine concentrations in limbic areas of suckling piglets (Sus scrofa) at different ages. J Vet Med A Physiol Pathol Clin Med 50:132–139PubMedGoogle Scholar
  35. Kliewer SA, Goodwin B, Willson TM (2002) The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism. Endocr Rev 23:687–702PubMedGoogle Scholar
  36. Langley-Evans SC (1997) Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens 15:537–544PubMedGoogle Scholar
  37. Lanz B, Kadereit B, Ernst S, Shojaati K, Causevic M, Frey BM, Frey FJ, Mohaupt MG (2003) Angiotensin II regulates 11beta-hydroxysteroid dehydrogenase type 2 via AT2 receptors. Kidney Int 64:970–977CrossRefPubMedGoogle Scholar
  38. Laplante DP, Barr RG, Brunet A, Galbaud du Fort G, Meaney ML, Saucier JF, Zelazo PR, King S (2004) Stress during pregnancy affects general intellectual and language functioning in human toddlers. Pediatr Res 56:400–410PubMedGoogle Scholar
  39. Lesage J, Hahn D, Leonhardt M, Blondeau B, Breant B, Dupouy JP (2002) Maternal undernutrition during late gestation-induced intrauterine growth restriction in the rat is associated with impaired placental GLUT3 expression, but does not correlate with endogenous corticosterone levels. J Endocrinol 174:37–43CrossRefPubMedGoogle Scholar
  40. Lesage J, Del-Favero F, Leonhardt M, Louvart H, Maccari S, Vieau D, Darnaudery M (2004) Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. J Endocrinol 181:291–296CrossRefPubMedGoogle Scholar
  41. Levitt NS, Lindsay RS, Holmes MC, Seckl JR (1996) Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology 64:412–418PubMedGoogle Scholar
  42. Liu L, Li A, Matthews SG (2001) Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects. Am J Physiol 280:E729-E739Google Scholar
  43. Lu NZ, Cidlowski JA (2004) The origin and functions of multiple human glucocorticoid receptor isoforms. Ann N Y Acad Sci 1024:102–123CrossRefPubMedGoogle Scholar
  44. MacLennan NK, James SJ, Melnyk S, Piroozi A, Jernigan S, Hsu JL, Janke SM, Pham TD, Lane RH (2004) Uteroplacental insufficiency alters DNA methylation, one-carbon metabolism, and histone acetylation in IUGR rats. Physiol Genomics 18:43–50PubMedGoogle Scholar
  45. McAlinden A, Moritz KM, Jefferies A, Cock M, Wintour EM, May CN, Dodic M (2004) Elevated sympathetic activity may play a role in adult hypertension induced by prenatal exposure to cortisol. 31st Annual Meeting of the Fetal and Neonatal Physiological Society, Tuscany, Italy, September 11–14, abstract 39Google Scholar
  46. McDonald TJ, Franko KL, Brown JM, Jenkins SL, Nathanielsz PW, Nijland MJ (2003) Betamethasone in the last week of pregnancy causes fetal growth retardation but not adult hypertension in rats. J Soc Gynecol Investig 10:469–473CrossRefPubMedGoogle Scholar
  47. McMullen S, Langley-Evans SC (2005) Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms.Am J Physiol 288:R85-R90. Google Scholar
  48. Mei Q, Richards K, Strong-Basalyga K, Fauty SE, Taylor A, Yamazaki M, Prueksaritanont T, Lin JH, Hochman J (2004) Using real-time quantitative TaqMan RT-PCR to evaluate the role of dexamethasone in gene regulation of rat P-glycoproteins mdr1a/1b and cytochrome P450 3A1/2. J Pharm Sci 93:2488–2496CrossRefPubMedGoogle Scholar
  49. Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B, Keightley PD, Bishop SM, Clarke AR, Bird A (2002) Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297:403–405CrossRefPubMedGoogle Scholar
  50. Molnar J, Howe DC, Nijland MJ, Nathanielsz PW (2003) Prenatal dexamethasone leads to both endothelial dysfunction and vasodilatory compensation in sheep. J Physiol (Lond) 547:61–66CrossRefGoogle Scholar
  51. Montaron MF, Piazza PV, Aurousseau C, Urani A, Le Moal M, Abrous DN (2003) Implication of corticosteroid receptors in the regulation of hippocampal structural plasticity. Eur J Neurosci 18:3105–111PubMedGoogle Scholar
  52. Moritz KM, Johnson K, Douglas-Denton R, Wintour EM, Dodic M (2002) Maternal glucocorticoid treatment programs alterations in the renin–angiotensin system of the ovine fetal kidney. Endocrinology 143:4455–4463CrossRefPubMedGoogle Scholar
  53. Moritz KM, Bertram JF, Douglas-Denton R, Wintour EM, Dodic M (2004) Reduced nephron number in the late gestation fetus after early maternal glucocorticoid treatment. 9th International Workshop on Developmental Nephrology, Barossa Valley, Australia, September, 2004Google Scholar
  54. Moritz KM, Jefferies AJ, Wintour EM, Dodic M (2005) Fetal renal and blood pressure responses to steroid infusion after early prenatal treatment with dexamethasone. Am J Physiol 288:R62-R66Google Scholar
  55. Moss TJ, Sloboda DM, Gurrin LC, Harding R, Challis JR, Newnham JP (2001) Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol 281:R960-R970Google Scholar
  56. Murphy VE, Zakar T, Smith R, Giles WB, Gibson PG, Clifton VL (2002) Reduced 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased birth weight centile in pregnancies complicated by asthma. J Clin Endocrinol Metab 87:1660–1668CrossRefPubMedGoogle Scholar
  57. Nicholls RD, Saitoh S, Horsthemke B (1998) Imprinting in Prader–Willi and Angelman syndromes. Trends Genet 14:194–200CrossRefPubMedGoogle Scholar
  58. Oostra BA, Willemsen R (2002) The X chromosome and fragile X mental retardation. Cytogenet Genome Res 99:257–264PubMedGoogle Scholar
  59. Ortiz LA, Quan A, Weinberg A, Baum M (2001) Effect of prenatal dexamethasone on rat renal development. Kidney Int 59:1663–1669CrossRefPubMedGoogle Scholar
  60. Ortiz LA, Quan A, Zarzar F, Weinberg A, Baum M (2003) Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 41:328–334CrossRefPubMedGoogle Scholar
  61. Prokhortchouk A, Hendrich B, Jorgensen H, Ruzov A, Wilm M, Georgiev G, Bird A, Prokhortchouk E (2001) The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev 15:1613–1618CrossRefPubMedGoogle Scholar
  62. Ravelli AC, Meulen JH van der, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP (1998) Glucose tolerance in adults after prenatal exposure to famine. Lancet 351:173–177CrossRefPubMedGoogle Scholar
  63. Rebuffat AG, Tam S, Nawrocki AR, Baker ME, Frey BM, Frey FJ, Odermatt A (2004) The 11-ketosteroid 11-ketodexamethasone is a glucocorticoid receptor agonist. Mol Cell Endocrinol 214:27–37CrossRefPubMedGoogle Scholar
  64. Reik W, Walter J (1998) Imprinting mechanisms in mammals. Curr Opin Genet Dev 8:154–164CrossRefPubMedGoogle Scholar
  65. Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093CrossRefPubMedGoogle Scholar
  66. Reznikov AG, Nosenko ND, Tarasenko LV (2004) Early postnatal effects of prenatal exposure to glucocorticoids on testosterone metabolism and biogenic monoamines in discrete neuroendocrine regions of the rat brain. Comp Biochem Physiol C Toxicol Pharmacol 138:169–175PubMedGoogle Scholar
  67. Richards EM, Hua Y, Keller-Wood M (2003) Pharmacology and physiology of ovine corticosteroid receptors. Neuroendocrinology 77:2–14CrossRefPubMedGoogle Scholar
  68. Risinger JI, Maxwell GL, Berchuck A, Barrett JC (2003) Promoter hypermethylation as an epigenetic component in type I and type II endometrial cancers. Ann N Y Acad Sci 983:208–212PubMedGoogle Scholar
  69. Rogerson FM, Yao YZ, Smith BJ, Dimopoulos N, Fuller PJ (2003) Determinants of spironolactone binding specificity in the mineralocorticoid receptor. J Mol Endocrinol 31:573–582CrossRefPubMedGoogle Scholar
  70. Roghair RD, Lamb FS, Miller Jr FJ, Scholz TD, Segar JL (2005) Early gestation dexamethasone programs enhanced postnatal ovine coronary artery vascular reactivity.Am J Physiol 288:R46-R53.Google Scholar
  71. Ruijter AJ de, Gennip AH van, Caron HN, Kemp S, Kuilenburg AB van (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749PubMedGoogle Scholar
  72. Rush LJ, Raval A, Funchain P, Johnson AJ, Smith L, Lucas DM, Bembea M, Liu TH, Heerema NA, Rassenti L, Liyanarachchi S, Davuluri R, Byrd JC, Plass C (2004) Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets. Cancer Res 64:2424–2433PubMedGoogle Scholar
  73. Seckl JR (1997) Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 62:89–94CrossRefPubMedGoogle Scholar
  74. Tokumaru Y, Yamashita K, Osada M, Nomoto S, Sun DI, Xiao Y, Hoque MO, Westra WH, Califano JA, Sidransky D (2004) Inverse correlation between cyclin A1 hypermethylation and p53 mutation in head and neck cancer identified by reversal of epigenetic silencing. Cancer Res 64:5982–5987PubMedGoogle Scholar
  75. Tresham JJ, Coghlan JP, Whitworth JA, Scoggins BA (1990) Lack of pressor response to intracerebroventricular infusion of aldosterone in sheep. Clin Exp Pharmacol Physiol 17:377–380PubMedGoogle Scholar
  76. Wade PA (2001) Methyl CpG-binding proteins and transcriptional repression. BioEssays 23:1131–1137CrossRefPubMedGoogle Scholar
  77. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004a) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854CrossRefPubMedGoogle Scholar
  78. Weaver IC, Diorio J, Seckl JR, Szyf M, Meaney MJ (2004b) Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci 1024:182–212CrossRefPubMedGoogle Scholar
  79. Weinstock M (1997) Does prenatal stress impair coping and regulation of hypothalamic–pituitary–adrenal axis? Neurosci Biobehav Rev 21:1–10PubMedGoogle Scholar
  80. Wilcoxon JS, Schwartz J, Aird F, Redei EE (2003) Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring. Am J Physiol 285:E31–E39PubMedGoogle Scholar
  81. Wintour EM, Alcorn D, Butkus A, Congiu M, Earnest L, Pompolo S, Potocnik SJ (1996) Ontogeny of hormonal and excretory function of the meso- and metanephros in the ovine fetus. Kidney Int 50:1624–1633PubMedGoogle Scholar
  82. Wintour EM, Johnson K, Koukoulas I, Moritz K, Tersteeg M, Dodic M (2003a) Programming the cardiovascular system, kidney and the brain—a review. Placenta 24 (Suppl A):S65–S71CrossRefPubMedGoogle Scholar
  83. Wintour EM, Moritz KM, Johnson K, Ricardo S, Samuel CS, Dodic M (2003b) Reduced nephron number in adult sheep, hypertensive as a result of prenatal glucocorticoid treatment. J Physiol (Lond) 549:929–935CrossRefGoogle Scholar
  84. Wintour EM, Liu H, Dodic M, Moritz KM (2004) Differential renal and cardiac gene expression in ovine fetuses programmed to become hypertensive adults by early glucocorticoid treatment. 12th International Congress of Endocrinology, LisbonGoogle Scholar
  85. Woods LL, Weeks DA, Rasch R (2004) Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis.Kidney Int 65:1339-1348CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Karen M. Moritz
    • 1
  • Wee Ming Boon
    • 2
  • E. Marelyn Wintour
    • 2
  1. 1.Department of Anatomy and Cell BiologyMonash UniversityClaytonAustralia
  2. 2.Department of PhysiologyMonash UniversityClaytonAustralia

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