Early Dexamethasone Treatment Induces Placental Apoptosis in Sheep

Glucocorticoid treatment given in late pregnancy in sheep resulted in altered placental development and function. An imbalance of placental survival and apoptotic factors resulting in an increased rate of apoptosis may be involved. We have now investigated the effects of dexamethasone (DEX) in early pregnancy on binucleate cells (BNCs), placental apoptosis, and fetal sex as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 105) were randomized to control (n = 56, 2 mL saline/ewe) or DEX treatment (n = 49, intramuscular injections of 0.14 mg/kg ewe weight per 12 hours over 48 hours) at 40 to 41 days of gestation (dG). Placentomes were collected at 50, 100, 125, and 140 dG. At 100 dG, DEX in females reduced BNC numbers, placental antiapoptotic (proliferating cell nuclear antigen), and increased proapoptotic factors (Bax, p53), associated with a temporarily decrease in fetal growth. At 125 dG, BNC numbers and apoptotic markers were restored to normal. In males, ovine placental lactogen-protein levels after DEX were increased at 50 dG, but at 100 and 140 dG significantly decreased compared to controls. In contrast to females, these changes were independent of altered BNC numbers or apoptotic markers. Early DEX was associated with sex-specific, transient alterations in BNC numbers, which may contribute to changes in placental and fetal development. Furthermore, in females, altered placental apoptosis markers may be involved.

[1]  W. Hay,et al.  Placental transport of nutrients and its implications for fetal growth. , 2019, Journal of reproduction and fertility. Supplement.

[2]  Julie Brown,et al.  Antenatal Corticosteroids for Accelerating Fetal Lung Maturation for Women at Risk of Preterm Birth , 2007, The Cochrane database of systematic reviews.

[3]  J. Newnham,et al.  Effects of tail docking and castration on stress responses in lambs and the influence of prenatal glucocorticoid treatment. , 2013, Reproduction, fertility, and development.

[4]  D. Sloboda,et al.  Early-life glucocorticoid exposure: the hypothalamic-pituitary-adrenal axis, placental function, and long-term disease risk. , 2013, Endocrine reviews.

[5]  J. Newnham,et al.  Fetal sex and preterm birth. , 2013, Placenta.

[6]  D. Sloboda,et al.  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. , 2013, Journal of developmental origins of health and disease.

[7]  D. Doherty,et al.  Effects of glucocorticoid treatment given in early or late gestation on growth and development in sheep , 2013, Journal of Developmental Origins of Health and Disease.

[8]  K. Moritz,et al.  Sex-Specific Effects of Prenatal Glucocorticoids on Placental Development , 2012 .

[9]  V. Padmanabhan,et al.  Developmental Programming: Impact of Prenatal Testosterone Excess on Ovarian Cell Proliferation and Apoptotic Factors in Sheep1 , 2012, Biology of reproduction.

[10]  J. Newnham,et al.  The Effects of Dexamethasone Treatment in Early Gestation on Hypothalamic–Pituitary–Adrenal Responses and Gene Expression at 7 Months of Postnatal Age in Sheep , 2012, Reproductive Sciences.

[11]  I. Jurisica,et al.  Sex-specific differences in placental global gene expression in pregnancies complicated by asthma. , 2011, Placenta.

[12]  D. Doherty,et al.  Differential appearance of placentomes and expression of prostaglandin H synthase type 2 in placentome subtypes after betamethasone treatment of sheep late in gestation. , 2011, Placenta.

[13]  Y. Lacasse,et al.  Role of fetal sex in the outcome of antenatal glucocorticoid treatment to prevent respiratory distress syndrome: systematic review and meta-analysis. , 2011, Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC.

[14]  Clive Osmond,et al.  Boys live dangerously in the womb , 2010, American journal of human biology : the official journal of the Human Biology Council.

[15]  V. Clifton Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. , 2010, Placenta.

[16]  D. Sloboda,et al.  Effects of maternal dexamethasone treatment in early pregnancy on pituitary-adrenal axis in fetal sheep. , 2009, Endocrinology.

[17]  P. V. van Zijl,et al.  Do Alterations in Placental 11β-Hydroxysteroid Dehydrogenase (11βHSD) Activities Explain Differences in Fetal Hypothalamic-Pituitary-Adrenal (HPA) Function Following Periconceptional Undernutrition or Twinning in Sheep? , 2009, Reproductive Sciences.

[18]  J. Fraser,et al.  BMC Molecular Biology BioMed Central , 2009 .

[19]  J. Seckl,et al.  Prenatal Stress, Glucocorticoids and the Programming of Adult Disease , 2009, Front. Behav. Neurosci..

[20]  I. McMillen,et al.  Intrauterine Growth Restriction and Differential Patterns of Hepatic Growth and Expression of IGF1, PCK2, and HSDL1 mRNA in the Sheep Fetus in Late Gestation1 , 2009, Biology of reproduction.

[21]  T. Hirvikoski,et al.  Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: does dexamethasone cause behavioural problems? , 2008, European journal of endocrinology.

[22]  D. Sloboda,et al.  Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny. , 2008, American journal of physiology. Endocrinology and metabolism.

[23]  P. Gluckman,et al.  Maternal betamethasone administration reduces binucleate cell number and placental lactogen in sheep. , 2007, The Journal of endocrinology.

[24]  E. Wintour,et al.  Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. , 2007, American journal of physiology. Endocrinology and metabolism.

[25]  T. Hirvikoski,et al.  Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. , 2007, The Journal of clinical endocrinology and metabolism.

[26]  S. Elmore Apoptosis: A Review of Programmed Cell Death , 2007, Toxicologic pathology.

[27]  J. Seckl,et al.  Mechanisms of Disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology , 2007, Nature Clinical Practice Endocrinology &Metabolism.

[28]  M. Simón,et al.  Differential efficacy of a cognitive – behavioral intervention versus pharmacological treatment in the management of fibromyalgic syndrome , 2006, Psychology, health & medicine.

[29]  A. Fowden,et al.  Programming placental nutrient transport capacity , 2006, The Journal of physiology.

[30]  V. Clifton,et al.  Effect of inhaled glucocorticoid treatment on placental 11β‐hydroxysteroid dehydrogenase type 2 activity and neonatal birthweight in pregnancies complicated by asthma , 2006, The Australian & New Zealand journal of obstetrics & gynaecology.

[31]  C. May,et al.  Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep , 2006, The Journal of physiology.

[32]  T. Scholz,et al.  Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[33]  I. Martín-Burriel,et al.  Positional and functional characterisation of apoptosis related genes belonging to the BCL2 family in sheep , 2005, Cytogenetic and Genome Research.

[34]  J. Seckl,et al.  Glucocorticoid exposure in late gestation in the rat permanently programs gender-specific differences in adult cardiovascular and metabolic physiology. , 2004, American journal of physiology. Endocrinology and metabolism.

[35]  M. Forest Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. , 2004, Human reproduction update.

[36]  A. Fowden,et al.  Ovine feto‐placental metabolism , 2004, The Journal of physiology.

[37]  P. Gibson,et al.  Maternal asthma is associated with reduced female fetal growth. , 2003, American journal of respiratory and critical care medicine.

[38]  S. Matthews,et al.  Glucocorticoids and sex-dependent development of brain glucocorticoid and mineralocorticoid receptors. , 2003, Endocrinology.

[39]  E. Wintour,et al.  Programming Effects of Short Prenatal Exposure to Dexamethasone in Sheep , 2002, Hypertension.

[40]  A. Fowden,et al.  The effect of a reversible period of adverse intrauterine conditions during late gestation on fetal and placental weight and placentome distribution in sheep. , 2002, Placenta.

[41]  S. Rees,et al.  Programming effects of short prenatal exposure to cortisol , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  A. Fowden,et al.  The effects of cortisol on the binucleate cell population in the ovine placenta during late gestation. , 2002, Placenta.

[43]  F. Speleman,et al.  Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes , 2002, Genome Biology.

[44]  K. A. Clarke,et al.  Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol. , 2002, The Journal of endocrinology.

[45]  M. Vidaud,et al.  Placental Growth Hormone and Lactogen Production by Perifused Ovine Placental Explants: Regulation by Growth Hormone-Releasing Hormone and Glucose , 2002, Biology of reproduction.

[46]  D. Sloboda,et al.  The fetal placental hypothalamic–pituitary–adrenal (HPA) axis, parturition and post natal health , 2001, Molecular and Cellular Endocrinology.

[47]  J. Kingdom,et al.  Undernutrition during the first half of gestation increases the predominance of fetal tissue in late-gestation ovine placentomes. , 2001, European journal of obstetrics, gynecology, and reproductive biology.

[48]  S. Handwerger,et al.  The Roles of Placental Growth Hormone and Placental Lactogen in the Regulation of Human Fetal Growth and Development , 2000, Journal of pediatric endocrinology & metabolism : JPEM.

[49]  F. Holsboer,et al.  Placental glucose transporter expression is regulated by glucocorticoids. , 1999, The Journal of clinical endocrinology and metabolism.

[50]  A. Reznikov,et al.  Prenatal stress and glucocorticoid effects on the developing gender-related brainProceedings of Xth International Congress on Hormonal Steroids, Quebec, Canada, 17–21 June 1998. , 1999, The Journal of Steroid Biochemistry and Molecular Biology.

[51]  S. Lajic,et al.  Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. , 1998, The Journal of clinical endocrinology and metabolism.

[52]  L. Penninga,et al.  Ovine placentome morphology: effect of high altitude, long-term hypoxia. , 1998, Placenta.

[53]  M. McGuire,et al.  Effect of chronic infusion of placental lactogen on ovine fetal growth in late gestation. , 1996, Domestic animal endocrinology.

[54]  M. New,et al.  Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: Results of a pilot study , 1995, Psychoneuroendocrinology.

[55]  A. Bell,et al.  Growth and metabolism of the ovine placenta during mid-gestation. , 1995, Placenta.

[56]  A. Ometto,et al.  Value of antenatal corticosteroid therapy in preterm birth. , 1995, Early human development.

[57]  W. H. Hall,et al.  Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes: NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes , 1995 .

[58]  E. Wintour,et al.  Effect of maternal glucocorticoid treatment on fetal fluids in sheep at 0.4 gestation. , 1994, The American journal of physiology.

[59]  R. Heap,et al.  Cellular dynamics of growth in sheep and goat synepitheliochorial placentomes: an autoradiographic study. , 1993, Journal of reproduction and fertility.

[60]  S. Kappes,et al.  Quantification and cellular localization of ovine placental lactogen messenger ribonucleic acid expression during mid- and late gestation. , 1992, Endocrinology.

[61]  P. Gluckman,et al.  The Nutritional Regulation of Circulating Placental Lactogen in Fetal Sheep , 1992, Pediatric Research.

[62]  F. Wooding,et al.  Current topic: the synepitheliochorial placenta of ruminants: binucleate cell fusions and hormone production. , 1992, Placenta.

[63]  B. McBride,et al.  Effect of heat stress on ovine placental growth in early pregnancy. , 1991, Journal of developmental physiology.

[64]  A. Bell,et al.  Growth and metabolism of the placenta after unilateral fetectomy in twin pregnant ewes. , 1991, Journal of developmental physiology.

[65]  R. Collier,et al.  Characterization of glycosylated bovine placental lactogen and the effect of enzymatic deglycosylation on receptor binding and biological activity. , 1990, Endocrinology.

[66]  L. Immken,et al.  Prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. , 1990, The New England journal of medicine.

[67]  M. Forest,et al.  Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. , 1984, The Journal of pediatrics.

[68]  F. Wooding The role of the binucleate cell in ruminant placental structure. , 1982, Journal of reproduction and fertility. Supplement.

[69]  P. Gluckman,et al.  Fetal sex and prenatal betamethasone therapy. , 1980, The Journal of pediatrics.

[70]  P. Gluckman,et al.  Hormone ontogeny in the ovine fetus. II. Ovine chorionic somatomammotropin in mid- and late gestation in the fetal and maternal circulations. , 1979, Endocrinology.

[71]  S. Handwerger,et al.  Development of the sheep as an animal model to study placental lactogen physiology. , 1975, The Journal of pediatrics.

[72]  G. Liggins,et al.  A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. , 1972, Pediatrics.

[73]  G. Alexander STUDIES ON THE PLACENTA OF THE SHEEP (OVIS ARIES L.). PLACENTAL SIZE. , 1964, Journal of reproduction and fertility.

[74]  T. Hirvikoski,et al.  Long-term outcome of prenatal treatment of congenital adrenal hyperplasia. , 2008, Endocrine development.

[75]  G. Burton,et al.  Synepitheliochorial Placentation : Ruminants (Ewe and Cow) , 2008 .

[76]  I. McMillen,et al.  Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep. , 2007, The Journal of endocrinology.

[77]  A. Fowden,et al.  Functional Significance and Cortisol Dependence of the Gross Morphology of Ovine Placentomes During Late Gestation1 , 2006, Biology of reproduction.

[78]  J. Ashwell,et al.  Glucocorticoids in T cell development and function*. , 2000, Annual review of immunology.

[79]  P. Gaynon,et al.  Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. , 1999, Advances in experimental medicine and biology.

[80]  N. Deutz,et al.  Transient umbilical cord occlusion in late-gestation fetal sheep results in hippocampal damage but not in cerebral arteriovenous difference for nitrite, a stable end product of nitric oxide. , 1999 .

[81]  R. Heap,et al.  Functional specialization in the ruminant placenta: evidence for two populations of fetal binucleate cells of different selective synthetic capacity. , 1996, Placenta.

[82]  H. Dörr,et al.  Prenatal dexamethasone treatment in pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: effect on midgestational amniotic fluid steroid levels. , 1993, The Journal of clinical endocrinology and metabolism.