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Altitude, Attitude and Adaptation

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Advances in Fetal and Neonatal Physiology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 814))

Abstract

The fetus has the extraordinary capacity to respond to stress during development, which, in a large part, is mediated by the hypothalamo- pituitary-adrenal (HPA) axis. Hypoxia represents a significant risk to fetal homeostasis and can occur in a wide range of settings including maternal smoking, preeclampsia, preterm labor and high altitude. To study fetal adaptation to chronic, gestational hypoxia, we developed a model of high-altitude, long-term hypoxia (LTH) in pregnant sheep. We discuss the role of LTH on the HPA axis and potential programming of adaptive responses. LTH causes significant activation of the hypothalamic paraventricular nucleus (PVN) and anterior pituitary. In marked contrast, there is an adaptive inhibition in the adrenal, thus balancing the potentially maladaptive centrally mediated responses to LTH. Additionally, we discuss effects of LTH on adipose tissue development. LTH enhances leptin production, which in turn has a regulatory role on the adrenal cortex. Importantly, LTH also has a significant impact on programming of adipose tissue function. Together, our studies show that LTH induces a number of adaptive responses in the ovine fetus. Although they may be beneficial during fetal life, these adaptations could prove to be deleterious in the postnatal period and adulthood.

Supported by National Institutes of Health Grants PO1HD31226, R01HD51951

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References

  1. Adachi K, Umezaki H, Kaushal KM, Ducsay CA. Long-term hypoxia alters ovine fetal endocrine and physiological responses to hypotension. Am J Physiol Regul Integr Comp Physiol. 2004;287:R209–17.

    Article  CAS  PubMed  Google Scholar 

  2. Imamura T, Umezaki H, Kaushal KM, Ducsay CA. Long-term hypoxia alters endocrine and physiologic responses to umbilical cord occlusion in the ovine fetus. J Soc Gynecol Investig. 2004;11:131–40.

    Article  CAS  PubMed  Google Scholar 

  3. Magyar DM, Fridshal D, Elsner CW, Glatz T, Eliot J, Klein AH, et al. Time-trend analysis of plasma cortisol concentrations in the fetal sheep in relation to parturition. Endocrinology. 1980;107:155–9.

    Article  CAS  PubMed  Google Scholar 

  4. 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:E1096–107.

    CAS  PubMed  Google Scholar 

  5. Myers DA, Myers TR, Grober MS, Nathanielsz PW. Levels of corticotropin-releasing hormone messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus and proopiomelanocortin mRNA in the anterior pituitary during late gestation in fetal sheep. Endocrinology. 1993;132:2109–16.

    CAS  PubMed  Google Scholar 

  6. Bell ME, Myers TR, Myers DA. Expression of proopiomelanocortin and prohormone convertase-1 and -2 in the late gestation fetal sheep pituitary. Endocrinology. 1998;139:5135–43.

    CAS  PubMed  Google Scholar 

  7. Matthews SG, Challis JR. Levels of pro-opiomelanocortin and prolactin mRNA in the fetal sheep pituitary following hypoxaemia and glucocorticoid treatment in late gestation. J Endocrinol. 1995; 147:139–46.

    Article  CAS  PubMed  Google Scholar 

  8. Bell ME, McDonald TJ, Myers DA. Proopiomelanocortin processing in the anterior pituitary of the ovine fetus after lesion of the hypothalamic paraventricular nucleus. Endocrinology. 2005; 146:2665–73.

    Article  CAS  PubMed  Google Scholar 

  9. Moritz KM, Butkus A, McFarlane AC, Albiston A, Salenmi R, Wintour EM. Regulation and function of steroid production by mid gestation ovine fetal adrenal cortex in vivo. Endocr Res. 1998;24:937–41.

    Article  CAS  PubMed  Google Scholar 

  10. Myers DA, Bell PA, Hyatt K. Glucocorticoid modulation of ACTH regulated cytochrome P450C17 (CYP17) expression in late gestation ovine fetal adrenocortical cells in vitro. J Soc Gynecol Investig. 2004;11(2 (Supplement)):211A.

    Google Scholar 

  11. Wintour EM. Developmental aspects of the hypothalamic-pituitary-adrenal axis. J Dev Physiol. 1984;6:291–9.

    CAS  PubMed  Google Scholar 

  12. McDonald TJ, Nathanielsz PW. Bilateral destruction of the fetal paraventricular nuclei prolongs gestation in sheep. Am J Obstet Gynecol. 1991;165:764–70.

    Article  CAS  PubMed  Google Scholar 

  13. Myers DA, McDonald TJ, Bell ME. Anterior pituitary ACTH biosynthesis decreases following lesion of the hypothalamic paraventricular nucleus (PVN) in the late gestation sheep fetus. J Soc Gynecol Investig. 2002;9(Supplement):Abstract #438.

    Google Scholar 

  14. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol. 2004;151 Suppl 3:U49–62.

    Article  CAS  PubMed  Google Scholar 

  15. Vaughan OR, Sferruzzi-Perri AN, Fowden AL. Maternal corticosterone regulates nutrient allocation to fetal growth in mice. J Physiol. 2012;590: 5529–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kutzler MA, Ruane EK, Coksaygan T, Vincent SE, Nathanielsz PW. Effects of three courses of maternally administered dexamethasone at 0.7, 0.75, and 0.8 of gestation on prenatal and postnatal growth in sheep. Pediatrics. 2004;113:313–9.

    Article  PubMed  Google Scholar 

  17. Miller SL, Sutherland AE, Supramaniam VG, Walker DW, Jenkin G, Wallace EM. Antenatal glucocorticoids reduce growth in appropriately grown and growth-restricted ovine fetuses in a sex-specific manner. Reprod Fertil Dev. 2012;24:753–8.

    Article  CAS  PubMed  Google Scholar 

  18. Field T, Diego M, Hernandez-Reif M, Gil K, Vera Y. Prenatal maternal cortisol, fetal activity and growth. Int J Neurosci. 2005;115:423–9.

    Article  CAS  PubMed  Google Scholar 

  19. France JT, Magness RR, Murry BA, Rosenfeld CR, Mason JI. The regulation of ovine placental steroid 17 alpha-hydroxylase and aromatase by glucocorticoid. Mol Endocrinol. 1988;2:193–9.

    Article  CAS  PubMed  Google Scholar 

  20. Challis JR, Sloboda D, Matthews SG, Holloway A, Alfaidy N, Patel FA, et al. The fetal placental hypothalamic-pituitary-adrenal (HPA) axis, parturition and post natal health. Mol Cell Endocrinol. 2001;185:135–44.

    Article  CAS  PubMed  Google Scholar 

  21. Braems GA, Matthews SG, Challis JR. Differential regulation of proopiomelanocortin messenger ribonucleic acid in the pars distalis and pars intermedia of the pituitary gland after prolonged hypoxemia in fetal sheep. Endocrinology. 1996;137:2731–8.

    CAS  PubMed  Google Scholar 

  22. Zehnder TJ, Valego NK, Schwartz J, White A, Rose JC. Regulation of bioactive and immunoreactive ACTH secretion by CRF and AVP in sheep fetuses. Am J Physiol. 1995;269:E1076–82.

    CAS  PubMed  Google Scholar 

  23. McMillen IC, Merei JJ, White A, Crosby S, Schwartz J. Increasing gestational age and cortisol alter the ratio of ACTH precursors:ACTH secreted from the anterior pituitary of the fetal sheep. J Endocrinol. 1995; 144:569–76.

    Article  CAS  PubMed  Google Scholar 

  24. Carr GA, Jacobs RA, Young IR, Schwartz J, White A, Crosby S, et al. Development of adrenocorticotropin-(1-39) and precursor peptide secretory responses in the fetal sheep during the last third of gestation. Endocrinology. 1995;136:5020–7.

    CAS  PubMed  Google Scholar 

  25. Schwartz J, Kleftogiannis F, Jacobs R, Thorburn GD, Crosby SR, White A. Biological activity of adrenocorticotropic hormone precursors on ovine adrenal cells. Am J Physiol. 1995;268:E623–9.

    CAS  PubMed  Google Scholar 

  26. Myers DA, Bell PA, Hyatt K, Mlynarczyk M, Ducsay CA. Long-term hypoxia enhances proopiomelanocortin processing in the near-term ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2005;288: R1178–84.

    Article  CAS  PubMed  Google Scholar 

  27. Ducsay CA, Myers DA. eNOS activation and NO function: differential control of steroidogenesis by nitric oxide and its adaptation with hypoxia. J Endocrinol. 2011;210:259–69.

    Article  CAS  PubMed  Google Scholar 

  28. Linnemann K, Malek A, Sager R, Blum WF, Schneider H, Fusch C. Leptin production and release in the dually in vitro perfused human placenta. J Clin Endocrinol Metab. 2000;85:4298–301.

    CAS  PubMed  Google Scholar 

  29. Yuen BS, Owens PC, Symonds ME, Keisler DH, McFarlane JR, Kauter KG, et al. Effects of leptin on fetal plasma adrenocorticotropic hormone and cortisol concentrations and the timing of parturition in the sheep. Biol Reprod. 2004;70:1650–7.

    Article  CAS  PubMed  Google Scholar 

  30. Ducsay CA, Hyatt K, Mlynarczyk M, Kaushal KM, Myers DA. Long-term hypoxia increases leptin receptors and plasma leptin concentrations in the late-gestation ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2006;291:R1406–13.

    Article  CAS  PubMed  Google Scholar 

  31. Ducsay CA, Furuta K, Vargas VE, Kaushal KM, Singleton K, Hyatt K, et al. Leptin receptor antagonist treatment ameliorates the effects of long-term maternal hypoxia on adrenal expression of key steroidogenic genes in the ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2013;304:R435–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Yuen BS, Owens PC, Muhlhausler BS, Roberts CT, Symonds ME, Keisler DH, et al. Leptin alters the structural and functional characteristics of adipose tissue before birth. FASEB J. 2003;17:1102–4.

    CAS  PubMed  Google Scholar 

  33. Scott J, Hyatt K, Myers DA. Developmental changes in adrenal leptin receptor expression and adrenocortical response to leptin in the ovine fetus. J Soc Gynecol Investig. 2005;12:239A.

    Google Scholar 

  34. Casteilla L, Forest C, Robelin J, Ricquier D, Lombet A, Ailhaud G. Characterization of mitochondrial-uncoupling protein in bovine fetus and newborn calf. Am J Physiol Endocrinol Metab. 1987;252:E627–36.

    CAS  Google Scholar 

  35. Clarke L, Buss DS, Juniper DT, Lomax MA, Symonds ME. Adipose tissue development during early postnatal life in ewe-reared lambs. Exp Physiol. 1997; 82:1015–27.

    Article  CAS  PubMed  Google Scholar 

  36. Devaskar SU, Anthony R, Hay Jr W. Ontogeny and insulin regulation of fetal ovine white adipose tissue leptin expression. Am J Physiol Regul Integr Comp Physiol. 2002;282:R431–8.

    CAS  PubMed  Google Scholar 

  37. Cannon B, Nedergaard JAN. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.

    Article  CAS  PubMed  Google Scholar 

  38. Gnanalingham MG, Mostyn A, Forhead AJ, Fowden AL, Symonds ME, Stephenson T. Increased uncoupling protein-2 mRNA abundance and glucocorticoid action in adipose tissue in the sheep fetus during late gestation is dependent on plasma cortisol and triiodothyronine. J Physiol. 2005;567:283–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Gnanalingham MG, Mostyn A, Symonds ME, Stephenson T. Ontogeny and nutritional programming of adiposity in sheep: potential role of glucocorticoid action and uncoupling protein-2. Am J Physiol Regul Integr Comp Physiol. 2005;289:R1407–15.

    Article  CAS  PubMed  Google Scholar 

  40. Myers DA, Hyatt K, Mlynarczyk M, Kaushal KM, Ducsay CA. Term hypoxia increases expression of transcription factors governing mitochondrial function and replication in peri-renal adipose tissue in the late gestation ovine fetus. Reprod Sci. 2009;16:331A.

    Google Scholar 

  41. Clarke I, Heasman L, Symonds ME. Influence of maternal dexamethasone administration on thermoregulation in lambs delivered by caesarean section. J Endocrinol. 1998;156:307–14.

    Article  CAS  PubMed  Google Scholar 

  42. Mostyn A, Pearce S, Budge H, Elmes M, Forhead AJ, Fowden AL, et al. Influence of cortisol on adipose tissue development in the fetal sheep during late gestation. J Endocrinol. 2003;176:23–30.

    Article  CAS  PubMed  Google Scholar 

  43. Symonds ME, Mostyn A, Pearce S, Budge H, Stephenson T. Endocrine and nutritional regulation of fetal adipose tissue development. J Endocrinol. 2003;179:293–9.

    Article  CAS  PubMed  Google Scholar 

  44. Myers DA, Hanson K, Mlynarczyk M, Kaushal KM, Ducsay CA. Long-term hypoxia modulates expression of key genes regulating adipose function in the late-gestation ovine fetus. Am J Physiol Regul Integr Comp Physiol. 2008;294:R1312–8.

    Article  CAS  PubMed  Google Scholar 

  45. Symonds ME, Budge H, Perkins AC, Lomax MA. Adipose tissue development—impact of the early life environment. Prog Biophys Mol Biol. 2011;106: 300–6.

    Article  CAS  PubMed  Google Scholar 

  46. Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Penicaud L, et al. Occurrence of brown adipocytes in rat white adipose tissue: molecular and morphological characterization. J Cell Sci. 1992;103: 931–42.

    CAS  PubMed  Google Scholar 

  47. Young P, Arch JR, Ashwell M. Brown adipose tissue in the parametrial fat pad of the mouse. FEBS Lett. 1984;167:10–4.

    Article  CAS  PubMed  Google Scholar 

  48. Ishibashi J, Seale P. Medicine. Beige can be slimming. Science. 2010;328:1113–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem. 2010;285:7153–64.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454:961–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Himms-Hagen J, Cui J, Danforth Jr E, Taatjes DJ, Lang SS, Waters BL, et al. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol. 1994;266:R1371–82.

    CAS  PubMed  Google Scholar 

  52. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121:96–105.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol. 2006;49:270–83.

    Article  PubMed  Google Scholar 

  54. Barker DJ. Obesity and early life. Obes Rev. 2007;8 Suppl 1:45–9.

    Article  PubMed  Google Scholar 

  55. Barker DJ, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006;2:700–7.

    Article  PubMed  Google Scholar 

  56. Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol. 2001;185:93–8.

    Article  CAS  PubMed  Google Scholar 

  57. Boney CM, Verma A, Tucker R, Vohr BR. Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics. 2005;115:e290–6.

    Article  PubMed  Google Scholar 

  58. Catalano PM. Obesity and pregnancy—the propagation of a viscous cycle? J Clin Endocrinol Metab. 2003;88:3505–6.

    Article  PubMed  Google Scholar 

  59. Oken E, Rifas-Shiman SL, Field AE, Frazier AL, Gillman MW. Maternal gestational weight gain and offspring weight in adolescence. Obstet Gynecol. 2008;112:999–1006.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Ducsay CA, Newby E, Cato C, Singleton K, Myers DA. Long term hypoxia during gestation alters perirenal adipose tissue in the lamb: a trigger for adiposity? 2013 J Devel Origins of Health and Disease 4 (supplement 2) DOHaD13–1194, S62. Journal of Developmental Origins of Health and Disease.4(Supplement 2):1194.

    Google Scholar 

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Myers, D.A., Ducsay, C.A. (2014). Altitude, Attitude and Adaptation. In: Zhang, L., Ducsay, C. (eds) Advances in Fetal and Neonatal Physiology. Advances in Experimental Medicine and Biology, vol 814. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1031-1_13

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