Home LiteratureArticle Details
PMID: 23220271 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first- and second-generation female offspring.

American journal of obstetrics and gynecology ·Vol. 208 ·No. 3 ·2013-03-00 ·Pages 217.e1-8

Long NM, Ford SP, Nathanielsz PW

Abstract

Synthetic glucocorticoid (sGC) administration to women threatening preterm delivery increases neonatal survival. Evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation programs offspring development. We examined fetal sGC multigenerational effects on F1 and F2 female offspring hypothalamo-pituitary-adrenal axis (HPAA) function. At 0.7 gestation, pregnant F0 ewes received 4 dexamethasone injections (2 mg, approximately 60 μg/kg(-1) per day(-1), 12 hours apart) or saline (control). F1 female offspring were bred to produce F2 female offspring. Postpubertal HPAA function was tested in F1 and F2 ewes. F1 and F2 ewe lambs showed reduced birthweight and morphometrics. Dexamethasone increased baseline but reduced stimulated HPAA activity in F1 and F2 female offspring. This is the first demonstration that sGC doses in the clinical range have multigenerational effects on hypothalamo-pituitary-adrenal activity in a precocial species, indicating the need for the study of long-term effects of fetal sGC exposure.

MeSH Terms
Animals Dexamethasone/pharmacology Female Glucocorticoids/pharmacology Hypothalamo-Hypophyseal System/drug effects,physiopathology Hypothalamus/drug effects,physiopathology Maternal-Fetal Exchange Pituitary Gland/drug effects,physiopathology Pituitary-Adrenal System/drug effects,physiopathology Pregnancy Pregnancy, Animal Prenatal Exposure Delayed Effects/physiopathology Sheep
Chemicals
Glucocorticoids Dexamethasone
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Long Nathan M
Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY, USA.
Ford Stephen P
Nathanielsz Peter W
References (44)
44 references, click to expand
  1. Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence?
    J Endocrinol. 2001 Sep;170(3):653-60 PMID: 11524246
  2. Premature delivery of foetal lambs infused with glucocorticoids.
    J Endocrinol. 1969 Dec;45(4):515-23 PMID: 5366112
  3. Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation.
    J Physiol. 2005 Jul 1;566(Pt 1):225-36 PMID: 15860532
  4. The effect of early to mid-gestational nutrient restriction on female offspring fertility and hypothalamic-pituitary-adrenal axis response to stress.
    J Anim Sci. 2010 Jun;88(6):2029-37 PMID: 20190172
  5. Prenatal betamethasone exposure results in pituitary-adrenal hyporesponsiveness in adult sheep.
    Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E61-70 PMID: 16882931
  6. Maternal, but not fetal, administration of corticosteroids restricts fetal growth.
    J Matern Fetal Med. 1999 May-Jun;8(3):81-7 PMID: 10338060
  7. Multiple courses of antenatal corticosteroids and outcome of premature neonates. North American Thyrotropin-Releasing Hormone Study Group.
    Am J Obstet Gynecol. 1999 Sep;181(3):709-17 PMID: 10486488
  8. Adverse effects of antenatal glucocorticoids on cerebral myelination in sheep.
    Obstet Gynecol. 2009 Jan;113(1):142-151 PMID: 19104370
  9. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.
    J Clin Invest. 1998 May 15;101(10):2174-81 PMID: 9593773
  10. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats.
    Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R34-8 PMID: 15178540
  11. Endocrine programming and fetal origins of adult disease.
    Trends Endocrinol Metab. 2002 Nov;13(9):363 PMID: 12367815
  12. Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids.
    Am J Obstet Gynecol. 2012 Sep;207(3):203.e1-8 PMID: 22939726
  13. Single and repetitive maternal glucocorticoid exposures reduce fetal growth in sheep.
    Am J Obstet Gynecol. 1998 May;178(5):880-5 PMID: 9609554
  14. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring.
    J Nutr. 2005 Jun;135(6):1382-6 PMID: 15930441
  15. Minireview: transgenerational inheritance of the stress response: a new frontier in stress research.
    Endocrinology. 2010 Jan;151(1):7-13 PMID: 19887563
  16. Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring of holocaust survivors.
    Arch Gen Psychiatry. 2007 Sep;64(9):1040-8 PMID: 17768269
  17. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes.
    JAMA. 1995 Feb 1;273(5):413-8 PMID: 7823388
  18. Prenatal synthetic glucocorticoid treatment changes DNA methylation states in male organ systems: multigenerational effects.
    Endocrinology. 2012 Jul;153(7):3269-83 PMID: 22564977
  19. Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function.
    J Physiol. 2008 Apr 15;586(8):2217-29 PMID: 18292131
  20. Elevated plasma cortisol in glucose-intolerant men: differences in responses to glucose and habituation to venepuncture.
    J Clin Endocrinol Metab. 2001 Mar;86(3):1149-53 PMID: 11238500
  21. Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age.
    J Physiol. 2005 May 15;565(Pt 1):137-47 PMID: 15790663
  22. Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function.
    Endocrinology. 2012 Jul;153(7):3295-307 PMID: 22564976
  23. Prenatal betamethasone exposure alters renal function in immature sheep: sex differences in effects.
    Am J Physiol Regul Integr Comp Physiol. 2010 Sep;299(3):R793-803 PMID: 20554936
  24. Effects of repeated maternal betamethasone administration on growth and hypothalamic-pituitary-adrenal function of the ovine fetus at term.
    J Endocrinol. 2000 Apr;165(1):79-91 PMID: 10750038
  25. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.
    Pediatrics. 1972 Oct;50(4):515-25 PMID: 4561295
  26. 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 May;13(5):425-31 PMID: 11328452
  27. Influence of sex and gonadal status of sheep on cortisol secretion in response to ACTH and on cortisol and LH secretion in response to stress: importance of different stressors.
    J Endocrinol. 2002 Apr;173(1):113-22 PMID: 11927390
  28. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure.
    Am J Physiol Regul Integr Comp Physiol. 2001 Sep;281(3):R960-70 PMID: 11507014
  29. 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 May;197(2):213-20 PMID: 18434351
  30. Antenatal dexamethasone and decreased birth weight.
    Obstet Gynecol. 2001 Apr;97(4):485-90 PMID: 11275014
  31. Influence of maternal undernutrition and overfeeding on cardiac ciliary neurotrophic factor receptor and ventricular size in fetal sheep.
    J Nutr Biochem. 2008 Jun;19(6):409-14 PMID: 17869083
  32. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy.
    Am J Obstet Gynecol. 2006 Sep;195(3):633-42 PMID: 16846587
  33. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life.
    BJOG. 2008 Sep;115(10):1243-9 PMID: 18715409
  34. Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects.
    Am J Physiol Endocrinol Metab. 2001 May;280(5):E729-39 PMID: 11287355
  35. The effect of prenatal betamethasone administration on postnatal ovine hypothalamic-pituitary-adrenal function.
    J Endocrinol. 2002 Jan;172(1):71-81 PMID: 11786375
  36. Brief undernutrition in late-gestation sheep programs the hypothalamic-pituitary-adrenal axis in adult offspring.
    Endocrinology. 2003 Jul;144(7):2933-40 PMID: 12810548
  37. Epigenetic modification of fetal baboon hepatic phosphoenolpyruvate carboxykinase following exposure to moderately reduced nutrient availability.
    J Physiol. 2010 Apr 15;588(Pt 8):1349-59 PMID: 20176628
  38. Epigenetic programming by maternal behavior.
    Nat Neurosci. 2004 Aug;7(8):847-54 PMID: 15220929
  39. Maternal high-fat diet promotes body length increases and insulin insensitivity in second-generation mice.
    Endocrinology. 2009 Nov;150(11):4999-5009 PMID: 19819967
  40. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth.
    Cochrane Database Syst Rev. 2006 Jul 19;(3):CD004454 PMID: 16856047
  41. Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans: a systematic review.
    Endocr Rev. 2009 Dec;30(7):753-89 PMID: 19837868
  42. Long-term effects of betamethasone on fetal development.
    Am J Obstet Gynecol. 1981 Dec 15;141(8):1053-64 PMID: 7315917
  43. The social environment and the epigenome.
    Environ Mol Mutagen. 2008 Jan;49(1):46-60 PMID: 18095330
  44. Repeated antenatal corticosteroids: size at birth and subsequent development.
    Am J Obstet Gynecol. 1999 Jan;180(1 Pt 1):114-21 PMID: 9914589
Article Info
Journal
American journal of obstetrics and gynecology
Abbr.
Am J Obstet Gynecol
ISSN
1097-6868
DOI
10.1016/j.ajog.2012.12.014
Published
2013-03-00
Epub
2012-00-07
Pages
217.e1-8
Language
English
Region
United States
NLM ID
0370476
PMCID
PMC3740770
Subset
IM
Grants
NICHD NIH HHS · P01 HD021350 · United States
NCRR NIH HHS · P20 RR016474 · United States
NCRR NIH HHS · P20- RR-16474-04 · United States
NICHD NIH HHS · HD 21350 · United States
External Links
PubMed source DOI: 10.1016/j.ajog.2012.12.014 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2