Role of catecholamines in maternal-fetal stress transfer in sheep.

OBJECTIVE We sought to evaluate whether in addition to cortisol, catecholamines also transfer psychosocial stress indirectly to the fetus by decreasing uterine blood flow (UBF) and increasing fetal anaerobic metabolism and stress hormones. STUDY DESIGN Seven pregnant sheep chronically instrumented with uterine ultrasound flow probes and catheters at 0.77 gestation underwent 2 hours of psychosocial stress by isolation. We used adrenergic blockade with labetalol to examine whether decreased UBF is catecholamine mediated and to determine to what extent stress transfer from mother to fetus is catecholamine dependent. RESULTS Stress induced transient increases in maternal cortisol and norepinephrine (NE). Maximum fetal plasma cortisol concentrations were 8.1 ± 2.1% of those in the mother suggesting its maternal origin. In parallel to the maternal NE increase, UBF decreased by maximum 22% for 30 minutes (P < .05). Fetal NE remained elevated for >2 hours accompanied by a prolonged blood pressure increase (P < .05). Fetuses developed a delayed and prolonged shift toward anaerobic metabolism in the presence of an unaltered oxygen supply. Adrenergic blockade prevented the stress-induced UBF decrease and, consequently, the fetal NE and blood pressure increase and the shift toward anaerobic metabolism. CONCLUSION We conclude that catecholamine-induced decrease of UBF is a mechanism of maternal-fetal stress transfer. It may explain the influence of maternal stress on fetal development and on programming of adverse health outcomes in later life especially during early pregnancy when fetal glucocorticoid receptor expression is limited.

[1]  J. Parer,et al.  Metabolic and cardiovascular effects on fetal sheep of sustained reduction of uterine blood flow. , 1985, The Journal of physiology.

[2]  J. Minton,et al.  Function of the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system in models of acute stress in domestic farm animals. , 1994, Journal of animal science.

[3]  A. López Bernal,et al.  Corticosteroid metabolism in vitro by human placenta, fetal membranes and decidua in early and late gestation. , 1981, Placenta.

[4]  S. Alahuhta,et al.  Placental and Fetal Hemodynamics After Labetalol or Pindolol in a Sheep Model of Increased Placental Vascular Resistance and Maternal Hypertension , 2009, Reproductive Sciences.

[5]  C. Jones,et al.  The effect of elevation of maternal plasma catecholamines on the fetus and placenta of the pregnant sheep. , 1986, Journal of developmental physiology.

[6]  J. Padbury,et al.  A comparative study of cardiovascular, endocrine and behavioural effects of betamethasone and dexamethasone administration to fetal sheep. , 1997, The Journal of physiology.

[7]  Z. W. A. L. A. Goonewardene.  The use of MIXED models in the analysis of animal experiments with repeated measures data , 2004 .

[8]  R. Anthony,et al.  The pregnant sheep as a model for human pregnancy. , 2008, Theriogenology.

[9]  C. Wood,et al.  Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation. , 2006, Physiological genomics.

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

[11]  G. Liggins,et al.  The role of cortisol in preparing the fetus for birth. , 1994, Reproduction, fertility, and development.

[12]  J. Padbury,et al.  Thresholds for physiological effects of plasma catecholamines in fetal sheep. , 1987, The American journal of physiology.

[13]  C. Rosenfeld,et al.  Large Conductance Ca2+-Activated K+ Channels Modulate Uterine α1-Adrenergic Sensitivity in Ovine Pregnancy , 2014, Reproductive Sciences.

[14]  S. Huffel,et al.  Antenatal Maternal Anxiety is Related to HPA-Axis Dysregulation and Self-Reported Depressive Symptoms in Adolescence: A Prospective Study on the Fetal Origins of Depressed Mood , 2008, Neuropsychopharmacology.

[15]  J. Padbury,et al.  Human placental norepinephrine transporter mRNA: expression and correlation with fetal condition at birth. , 1997, Placenta.

[16]  G. Burton,et al.  HYPOXIA-REOXYGENATION; A POTENTIAL SOURCE OF PLACENTAL OXIDATIVE STRESS IN NORMAL PREGNANCY AND PREECLAMPSIA , 2003 .

[17]  T. Kute,et al.  Glucocorticoid receptors in sheep brain tissues during development. , 1985, The American journal of physiology.

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

[19]  A. Rudolph,et al.  Effect of β-Adrenergic Stimulation on Oxygen Metabolism in the Fetal Lamb , 1999, Pediatric Research.

[20]  C. Deal,et al.  Tracing the origins of "fetal origins" of adult diseases: programming by oxidative stress? , 2006, Medical hypotheses.

[21]  A. Charil,et al.  Prenatal stress and brain development , 2010, Brain Research Reviews.

[22]  R. Robinson,et al.  Plasma catecholamines in foetal and adult sheep. , 1975, The Journal of physiology.

[23]  M. Ui,et al.  Activation of the Cori cycle by epinephrine. , 1977, The American journal of physiology.

[24]  H. Beydoun,et al.  Physical and mental health outcomes of prenatal maternal stress in human and animal studies: a review of recent evidence. , 2008, Paediatric and perinatal epidemiology.

[25]  D. Rurak,et al.  Pharmacokinetics and pharmacodynamics of labetalol in the pregnant sheep. , 1992, The Journal of pharmacology and experimental therapeutics.

[26]  N. Fisk,et al.  Human Fetal and Maternal Noradrenaline Responses to Invasive Procedures , 1999, Pediatric Research.

[27]  J. Padbury,et al.  Placental norepinephrine transporter development in the ovine fetus. , 1997, Placenta.

[28]  J. Padbury,et al.  Plasma epinephrine appearance and clearance rates in fetal and newborn sheep. , 1993, The American journal of physiology.

[29]  C. Rosenfeld,et al.  Systemic and uterine responses to alpha-adrenergic stimulation in pregnant and nonpregnant ewes. , 1986, American journal of obstetrics and gynecology.

[30]  C. Jones,et al.  The metabolic and endocrine effects of circulating catecholamines in fetal sheep. , 1978, The Journal of physiology.

[31]  M. Roizen,et al.  Uterine Blood Flow and Plasma Norepinephrine Changes during Maternal Stress in the Pregnant Ewe , 1979, Anesthesiology.

[32]  J. Seckl,et al.  Distinct Ontogeny of Glucocorticoid and Mineralocorticoid Receptor and 11β-Hydroxysteroid Dehydrogenase Types I and II mRNAs in the Fetal Rat Brain Suggest a Complex Control of Glucocorticoid Actions , 1998, The Journal of Neuroscience.

[33]  T. Rosenkrantz,et al.  Consequences of Perturbations of Fetal Fuels in Ovine Pregnancy , 1985, Diabetes.

[34]  O. Witte,et al.  Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus–pituitary–adrenal axis in sheep , 2013, Stress.

[35]  J. Seckl,et al.  Ontogeny of glucocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. , 2004, The Journal of endocrinology.

[36]  M. Heymann,et al.  Relationships between Pressure and Flow in the Umbilical and Uterine Circulations of the Sheep , 1976, Circulation research.

[37]  V. Glover,et al.  Prenatal stress and the programming of the HPA axis , 2010, Neuroscience & Biobehavioral Reviews.

[38]  C. Rosenfeld,et al.  Systemic and uterine responses to α-adrenergic stimulation in pregnant and nonpregnant ewes , 1986 .

[39]  S. Saarikoski.  Fate of noradrenaline in the human foetoplacental unit. , 1974, Acta physiologica Scandinavica. Supplementum.

[40]  J. Challis,et al.  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. , 1994, The Journal of endocrinology.

[41]  Maarten Mennes,et al.  Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review , 2005, Neuroscience & Biobehavioral Reviews.

[42]  J. Padbury,et al.  Placental norepinephrine clearance: in vivo measurement and physiological role. , 1995, The American journal of physiology.

[43]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[44]  A. Boissy,et al.  Effects of repeated stress during pregnancy in ewes on the behavioural and physiological responses to stressful events and birth weight of their offspring , 2004 .

[45]  J. Unruh,et al.  Influence of repeated restraint and isolation stress and electrolyte administration on pituitary-adrenal secretions, electrolytes, and other blood constituents of sheep. , 1993, Journal of animal science.

[46]  G. Meschia,et al.  Response of Ovine Uterine Blood Flow to Epinephrine and Norepinephrine 1 , 1974, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[47]  T. Siddiqi,et al.  Maternal and Fetal Cardiovascular Responses of the Normotensive and Hypertensive Pregnant Sheep to Parenteral Labetalol , 1990 .