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Intergenerational Influence of Antenatal Betamethasone on Growth, Growth Factors, and Neurological Outcomes in Rats

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Abstract

Antenatal steroids suppress growth in the fetus and newborn. Although weight deficits are regained by weaning, studies show that intrauterine growth restriction with postnatal “catch-up” growth is a risk factor for hypertension, insulin resistance, and ischemic heart disease in adult life, with multigenerational consequences. We tested the hypothesis that fetal exposure to betamethasone suppresses fetal growth in the F1 pups and their untreated F2 offspring. Timed pregnant rats received a single two-dose course of intramuscular betamethasone (0.25 mg/kg/day) on days 17 and 18 of gestation. Matched controls received equivalent volumes sterile normal saline. The first-generation (F1) offspring were studied at term, P21, and P70, or mated at P60 to produce the following subgroups: (1) saline male/saline female (SM/SF), (2) betamethasone (B) male/BFemale (BM/BF), (3) BM/SF, and (4) SM/BF. The unexposed second-generation (F2) offspring were examined at birth and P70. Growth, neurological outcomes, and growth factors were determined. At birth, the F1 pups exposed to B were significantly growth suppressed compared with the controls, with correspondingly lower blood glucose, insulin, IGF-I, corticosterone, and leptin levels and delayed neurological outcomes. Catchup growth occurred at P21, surpassing that of the control group. By P70, growth was comparable, but glucose was higher, insulin was lower, and memory was retarded in the B group, and transmitted to the unexposed F2 offspring of B-exposed rats. Antenatal betamethasone has sustained metabolic and neurological effects that may impact the unexposed offspring. Whether these intergenerational effects reverse in future generations remain to be determined.

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Abbreviations

Sal:

saline

SM/SF:

saline-treated male/saline-treated female

BM/BF:

betamethasone-treated male/betamethasone-treated female

BM/SF:

betamethasone-treated male/saline-treated female

SM/BF:

saline-treated male/betamethasone-treated female

P0:

day of birth

P21:

21 days postnatal age

P70:

70 days postnatal age

RDS:

respiratory distress syndrome

GCs:

glucocorticoids

IM:

intramuscular

SGA:

small for gestational age

AGA:

appropriate for gestational age

IGF:

insulin-like growth factor

IGFR:

insulin-like growth factor receptor

IGFBP:

insulin-like growth factor binding protein

IUGR:

intrauterine growth restriction

GH:

growth hormone

F1:

first generation

F2:

second generation

ANOVA:

analysis of variance

SEM:

standard error of the mean

SPSS:

Statistical Package for the Social Sciences

HPA:

hypothalamic-pituitary-adrenal

11β-HSD:

11β-hydroxysteroid dehydrogenase

References

  1. NIH Consensus. JAMA. 1995;l273:413–8.

    Google Scholar 

  2. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for the prevention of RDS in preterm infants. Pediatrics. 1972;50:515–25.

    CAS  PubMed  Google Scholar 

  3. Gilstrap LC, Christensen R, Clewell WH, D’Alton ME, Davidson EC Jr, Escobedo MB, 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. JAMA. 1995;273:413–8.

    Google Scholar 

  4. Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, et al. Long-term outcomes after repeat doses of antenatal corticosteroids. New Engl J Med. 2007;357:1190–8.

    CAS  PubMed  Google Scholar 

  5. Jobe A. Glucocorticoids in perinatal medicine: misguided rockets? Editorial Comments. J Pediatr. 2000;137:1–2.

    CAS  PubMed  Google Scholar 

  6. Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration on the prevention of respiratory distress syndrome. Am J Obstet Gyn. 1981;141:276–87.

    Google Scholar 

  7. Delibas IB, Ingec M, Yapca OE. Does antenatal betamethasone have negative effects on fetal activities and hemodynamics in cases of preeclampsia without severe features? A prospective, placebo-controlled, randomized study. J Matern Fetal Neonatal Med. 2017;30:2671–8.

    CAS  PubMed  Google Scholar 

  8. Koenen SV, Mulder EJ, Wijnberger LD, Visser GH. Transient loss of the diurnal rhythms of fetal movements, heart rate, and its variation after maternal betamethasone administration. Pediatr Res. 2005;57:662–6.

    CAS  PubMed  Google Scholar 

  9. French NP, Hagan R, Evans SF, Godfrey M, Newnham JP. Repeated antenatal corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol. 1999;180:114–21.

    CAS  PubMed  Google Scholar 

  10. Ikegami M. Repetitive prenatal steroids improve lung function and decrease growth in preterm lambs. Am J Respir Crit Care Med. 1997;156:178–84.

    CAS  PubMed  Google Scholar 

  11. Uno H. Brain damage induced by prenatal exposure to dexamethasone in fetal rhesus macaques. I. Hippocampus. Brain Res Dev Brain Res. 1990;53:157–67.

    CAS  PubMed  Google Scholar 

  12. Barrada MI, Blomquist CH, Kotts C. The effect of betamethasone on fetal development in the rabbit. Am J Obstet Gynecol. 1980;136:234–8.

    CAS  PubMed  Google Scholar 

  13. Brehier A, Benson BH. Corticosteroid induction of phosphatidic acid phosphatase in fetal rabbit lung. Biochem Biophys Res Commun. 1977;77:883–90.

    CAS  PubMed  Google Scholar 

  14. Gumbinas M, Oda M, Huttenlocher P. The effect of corticosteroids on myelination of the developing rat brain. Biol Neonate. 1973;22:355–66.

    CAS  PubMed  Google Scholar 

  15. Howard E. Reductions in size and total DNA of cerebrum and cerebellum in adult mice after corticosterone treatment in infancy. Exp Neurol. 1968;22:191–208.

    CAS  PubMed  Google Scholar 

  16. Howard E, Benjamin JA. DNA, ganglioside and sulfatide in brains of rats given corticosterone in infancy, with an estimate of cell loss during development. Brain Res. 1975;92:73–87.

    CAS  PubMed  Google Scholar 

  17. Weichsel MF. Glucocorticoid effect upon thymidine kinase in the developing cerebellum. Pediatr Res. 1974;8:843–7.

    CAS  PubMed  Google Scholar 

  18. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, et al. Fetal and infant growth and impaired glucose tolerance at age 64. Br Med J. 1991;303:1019–22.

    CAS  Google Scholar 

  19. Holmes R. Fetal and maternal plasma IGF and binding proteins in pregnant with or retarded fetal growth. Early Human Dev. 1997;49:7–17.

    CAS  Google Scholar 

  20. Le Roith D. Seminars in medicine of the Beth Israel Deaconess Medical Center. Insulin-like growth factors. N Engl J Med. 1997;336:633–40.

    PubMed  Google Scholar 

  21. Baker J. Role of insulin and IGF in embryonic and postnatal growth. Cell. 1993;75:73–82.

    CAS  PubMed  Google Scholar 

  22. Brooks AN, Hagan DM, Howe DC. Neuroendocrine regulation of pituitary-adrenal function during fetal life. Eur J Endocrinol. 1996;135:153–65.

    CAS  PubMed  Google Scholar 

  23. McMorris FA, Smith TM. IGF-1/somatomedin C, a potent inducer of oligodendrocyte development. Proc Natl Acad Sci U S A. 1986;83:822–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Cianfarani C. IGF-1, BP-1 are related to cortisol in human cord blood. Euro J Endocrinol. 1998;138:524–9.

    CAS  Google Scholar 

  25. Hills FA, Gunn LK, Hardiman P, Thamaratnam S, Chard T. IGFBP-1 in the placenta, membranes and fetal circulation: levels at term and preterm, delivery. Early Human Dev. 1996;44:71–6.

    CAS  Google Scholar 

  26. Hills FA, Crawford R, Harding S, Farkas A, Chard T. The effect of labor on maternal and fetal levels of IGFBP-1. Am J Obstet Gynecol. 1994;171:1292–5.

    CAS  PubMed  Google Scholar 

  27. Drake AJ, Walker BR, Seckl JR. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Com Physiol. 2005;288:R34–8.

    CAS  Google Scholar 

  28. Drake AJ, Walker BR. The intergenerational effects of fetal programming: non-genomic mechanisms for the inheritance of low birth weight and cardiovascular risk. J Endocrinol. 2004;180:1–16.

    CAS  PubMed  Google Scholar 

  29. Iqbal M, Moisiadis VG, Kostaki A, Matthews SG. Transgenerational effects of prenatal synthetic glucocorticoids on hypothalamic-pituitary-adrenal function. Endocrinology. 2012;153:3295–307.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Constantinof A, Moisiadis VG, Matthews SG. Programming of stress pathways: a transgenerational perspective. J Steroid Biochem Mol Biol. 2016;160:175–80.

    CAS  PubMed  Google Scholar 

  31. Mewar R, McMorris FA. Expression of insulin-like growth factor binding protein messenger RNAs in developing rat oligodendrocytes and astrocytes. J Neurosci Res. 1997;50:721–8.

    CAS  PubMed  Google Scholar 

  32. Gramsenbergen A, Mulder EJH. The influence of betamethasone and dexamethasone on motor development in young rats. Pediatr Res. 1998;44:105–10.

    Google Scholar 

  33. Dalm S, Grootendorst S, de Kloet ER, Oitzl MS. Quantification of search patterns in the Morris water maze. Behav Res Methods Instrum Comput. 2000;32:134–9.

    CAS  PubMed  Google Scholar 

  34. Oitzl MS, de Kloet ER, Joels M, Schmid W, Cole TJ. Spatial learning deficits in mice with a targeted glucocorticoid receptor gene disruption. Eur J Neurosci. 1997;9:2284–96.

    CAS  PubMed  Google Scholar 

  35. Tucker LB, Velosky AG, McCabe JT. Applications of the Morris water maze in translational traumatic brain injury research. Neurosci Biobehav Rev. 2018;88:187–200.

    PubMed  Google Scholar 

  36. Cotterell M, Balazs R, Johnson AL. Effects of corticosteroids on the biochemical maturation of rat brain: postnatal cell formation. J Neurochem. 1972;19:2151–61.

    Google Scholar 

  37. Walker SM, Fitzgerald M, Hathway GJ. Surgical injury in the neonatal rat alters the adult pattern of descending modulation from the rostroventral medulla. Anesthesiology. 2015;122:1391–400.

    PubMed  PubMed Central  Google Scholar 

  38. Thomassin H, Flavin M, Espinas ML, Grange T. Glucocorticoid-induced DNA methylation and gene memory during development. EMBO J. 2001;20:1974–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Pembrey M. Imprinting and transgenerational modulation of gene expression; human growth as a model. Acta Genet Med Gemellol. 1996;45:111–25.

    CAS  PubMed  Google Scholar 

  40. Crudo A, Petropoulos S, Moisiadis VG, Iqbal M, Kostaki A, Machnes Z, et al. Prenatal synthetic glucocorticoid treatment changes DNA methylation states in male organ systems: multigenerational effects. Endocrinology. 2012;153:3269–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yao Y, Robinson AM, Zucchi FC, et al. Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes. BMC Med. 2014, 12:121.

  42. Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C. Parental genomic imprinting of the human IGF2 gene. Nat Genet. 1993;4:98–101.

    CAS  PubMed  Google Scholar 

  43. Rodgers AB, Morgan CP, Leu NA, Bale TL. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. PNAS. 2015;112:13699–704.

    CAS  PubMed  Google Scholar 

  44. Doyle LW, Ford GW, Rickards AL, et al. Antenatal corticosteroids and outcome at 14 years of age in children with birth weight less than 1501 grams. Pediatrics. 2000;106:E2.

    CAS  PubMed  Google Scholar 

  45. Washburn LK, Nixon PA, Snively BM, et al. Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight. Pediatr Res. 2017;82:697–703.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Stark MJ, Wright IM, Clifton VL. Sex-specific alterations in placental 11beta-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone. Am J Physiol Regul Integr Comp Physiol. 2009;297:R510–4.

    CAS  PubMed  Google Scholar 

  47. Saif Z, Hodyl NA, Stark MJ, et al. Expression of eight glucocorticoid receptor isoforms in the human preterm placenta vary with fetal sex and birthweight. Placenta. 2015;36:723–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Stark MJ, Hodyl NA, Wright IMR, Clifton VL. Influence of sex and glucocorticoid exposure on preterm placental pro-oxidant-antioxidant balance. Placenta. 2011;32:865–70.

    CAS  PubMed  Google Scholar 

  49. Long NM, Shasa DR, Ford SP, Nathanielsz PW. Growth and insulin dynamics in two generations of female offspring of mothers receiving a single course of synthetic glucocorticoids. Am J Obstet Gynecol. 2012;203:e1–8.

    Google Scholar 

  50. Long NM, Ford SP, Nathanielsz PW. Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first- and second-generation female offspring. Am J Obstet Gynecol. 2013;217:e1–8.

    Google Scholar 

  51. Church MW, Adams BR, Anumba JI, Jackson DA, Kruger ML, Jen KL. Repeated antenatal corticosteroid treatments adversely affect neural transmission time and auditory thresholds in laboratory rats. Neurotoxicol Teratol. 2012;34:196–205.

    CAS  PubMed  Google Scholar 

  52. Moisiadis VG, Matthews SG. Glucocorticoids and fetal programming part 2: mechanisms. Nat Rev. 2014;10:403–11.

    CAS  Google Scholar 

  53. Braun T, Challis JR, Newnham JP, Sloboda DM. Early-life glucocorticoid exposure: the hypothalamic-pituitary-adrenal axis, placental function, and long-term disease risk. Endocrine Rev. 2013;34:885–916.

    CAS  Google Scholar 

  54. Price WA, Stiles AE, Moats-Staats BM, D’Ercole AJ. Gene expression of insulin-like growth factors (IGFs), the type 1IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation. Endocrinology. 1992;130:1424–32.

    CAS  PubMed  Google Scholar 

  55. Lassarre C, Hardouin S, Daffos F, Forestier F, Frankenne F, Binoux M. Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res. 1991;29:219–25.

    CAS  PubMed  Google Scholar 

  56. Sara VR, Hall K. Insulin-like growth factors and their binding proteins. Physiol Rev. 1990;70:591–614.

    CAS  PubMed  Google Scholar 

  57. Rappolee DA, Sturm KS, Behrendtsen O, Schultz GA, Pedersen RA, Werb Z. Insulin-like growth factor II acts through an endogenous growth pathway regulated by imprinting in early mouse embryos. Genes Dev. 1992;6:939–52.

    CAS  PubMed  Google Scholar 

  58. Nilsson O, Marino R, De Luca F, Phillip M, Baron J. Endocrine regulation of the growth plate. Horm Res. 2005;64:157–65.

    CAS  PubMed  Google Scholar 

  59. Hamrick MW, Dukes A, Arounleut P, Davis C, Periyasamy-Thandavan S, Mork S, et al. The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice. Exp Gerontol. 2015;70:92–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Harada I, Tsutsumi O, Momoeda M, Horikawa R, Yasunaga T, Tanaka T, et al. Comparative concentrations of growth hormone-binding protein in maternal circulation, fetal circulation, and amniotic fluid. Endocr J. 1997;44:111–6.

    CAS  PubMed  Google Scholar 

  61. Kargi AY, Merriam GR. Diagnosis and treatment of growth hormone deficiency in adults. Nat Rev Endocrinol. 2013;9:335–45.

    CAS  PubMed  Google Scholar 

  62. Ibañez De Cáceres I, Villanúa MA, Soto L, Martin AI, López-Calderón A. IGF-I and IGF-I-binding proteins in rats with adjuvant-induced arthritis given recombinant human growth hormone. J Endocrinol. 2000;165:537–44.

    PubMed  Google Scholar 

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Funding

This work was supported by Memorial Health Services Research Foundation, Long Beach, CA, USA.

Author information

Author notes

  1. Maria A. Abrantes

    Present address: Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Kaiser Permanente, Irvine, CA, USA

  2. Arwin M. Valencia

    Present address: Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saddleback Memorial Medical Center, Laguna Hills, CA, USA

  3. Kay D. Beharry

    Present address: Departments of Pediatrics & Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

Authors and Affiliations

  1. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, Irvine Medical Center, Orange, CA, USA

    Maria A. Abrantes, Arwin M. Valencia & Kay D. Beharry

  2. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Long Beach Memorial Medical Center, Long Beach, CA, USA

    Maria A. Abrantes, Arwin M. Valencia, Fayez Bany-Mohammed & Kay D. Beharry

  3. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

    Jacob V. Aranda & Kay D. Beharry

  4. Department of Ophthalmology, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY, USA

    Jacob V. Aranda & Kay D. Beharry

  5. Department of Pediatrics & Ophthalmology, Neonatal-Perinatal Medicine Clinical & Translational Research Labs, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 49, Brooklyn, NY, 11203, USA

    Kay D. Beharry

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  1. Maria A. Abrantes
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Corresponding author

Correspondence to Kay D. Beharry.

Ethics declarations

All experiments were approved by the Institutional Animal Care and Use Committee, Long Beach Memorial Medical Center, Long Beach, CA. Animals were cared for according to the guidelines outlined by the Guide for the Care and Use of Laboratory Animals (National Research Council). Euthanasia of the animals was conducted according to the guidelines of the American Veterinary Medical Association (AVMA Panel).

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The authors declare that they have no conflict of interest.

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Abrantes, M.A., Valencia, A.M., Bany-Mohammed, F. et al. Intergenerational Influence of Antenatal Betamethasone on Growth, Growth Factors, and Neurological Outcomes in Rats. Reprod. Sci. 27, 418–431 (2020). https://doi.org/10.1007/s43032-019-00073-w

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