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Maternal l-glutamine supplementation prevents prenatal alcohol exposure-induced fetal growth restriction in an ovine model

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Abstract

Prenatal alcohol exposure is known to cause fetal growth restriction and disturbances in amino acid bioavailability. Alterations in these parameters can persist into adulthood and low birth weight can lead to altered fetal programming. Glutamine has been associated with the synthesis of other amino acids, an increase in protein synthesis and it is used clinically as a nutrient supplement for low birth weight infants. The aim of this study was to explore the effect of repeated maternal alcohol exposure and l-glutamine supplementation on fetal growth and amino acid bioavailability during the third trimester-equivalent period in an ovine model. Pregnant sheep were randomly assigned to four groups, saline control, alcohol (1.75–2.5 g/kg), glutamine (100 mg/kg, three times daily) or alcohol + glutamine. In this study, a weekend binge drinking model was followed where treatment was done 3 days per week in succession from gestational day (GD) 109–132 (normal term ~147). Maternal alcohol exposure significantly reduced fetal body weight, height, length, thoracic girth and brain weight, and resulted in decreased amino acid bioavailability in fetal plasma and placental fluids. Maternal glutamine supplementation successfully mitigated alcohol-induced fetal growth restriction and improved the bioavailability of glutamine and glutamine-related amino acids such as glycine, arginine, and asparagine in the fetal compartment. All together, these findings show that l-glutamine supplementation enhances amino acid availability in the fetus and prevents alcohol-induced fetal growth restriction.

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Abbreviations

FAS:

Fetal alcohol syndrome

FASD:

Fetal alcohol spectrum disorders

GD:

Gestational day

IUGR:

Intra uterine growth restriction

References

  • Abel EL, Dintcheff BA (1978) Effects of prenatal alcohol exposure on growth and development in rats. J Pharmacol Exp Ther 207(3):916–921

    CAS  PubMed  Google Scholar 

  • Als H, Tronick E, Adamson L, Brazelton TB (1976) The behavior of the full-term but underweight newborn infant. Developmental medicine and child neurology 18(5):590–602

    Article  CAS  PubMed  Google Scholar 

  • Assaad H, Zhou L, Carroll RJ, Wu G (2014) Rapid publication-ready MS-Word tables for one-way ANOVA. Springerplus 3: 474

  • Assaad H, Hou YQ, Zhou L, Carroll RJ, Wu G (2015) Rapid publication-ready MS-Word tables for two-way ANOVA. Springerplus 4: 33

  • Barker DJ (1994) Maternal and fetal origins of coronary heart disease. J Royal Coll Phys Lond 28(6):544–551

    CAS  Google Scholar 

  • Caetano R, Ramisetty-Mikler S, Floyd LR, McGrath C (2006) The epidemiology of drinking among women of child-bearing age. Alcohol Clin Exp Res 30(6):1023–1030

    Article  PubMed  Google Scholar 

  • Coles CD, Brown RT, Smith IE, Platzman KA, Erickson S, Falek A (1991) Effects of prenatal alcohol exposure at school age. I. Physical and cognitive development. Neurotoxicol Teratol 13(4):357–367

    Article  CAS  PubMed  Google Scholar 

  • Cooper C, Westlake S, Harvey N, Dennison E (2009) Developmental origins of osteoporotic fracture. Adv Exp Med Biol 639:217–236. doi:10.1007/978-1-4020-8749-3_16

    Article  CAS  PubMed  Google Scholar 

  • Cornelius MD, Goldshmidt L, Taylor PM, Day NL (1999) Prenatal alcohol use among teenagers: effects on neonatal outcomes. Alcohol Clin Experiment Res 23(7):1238–1244

    Article  CAS  Google Scholar 

  • Coster J, McCauley R, Hall J (2004) Glutamine: metabolism and application in nutrition support. Asia Pac J Clin Nutr 13(1):25–31

    CAS  PubMed  Google Scholar 

  • Day NL, Richardson G, Robles N, Sambamoorthi U, Taylor P, Scher M, Stoffer D, Jasperse D, Cornelius M (1990) Effect of prenatal alcohol exposure on growth and morphology of offspring at 8 months of age. Pediatrics 85(5):748–752

    CAS  PubMed  Google Scholar 

  • Day NL, Zuo Y, Richardson GA, Goldschmidt L, Larkby CA, Cornelius MD (1999) Prenatal alcohol use and offspring size at 10 years of age. Alcohol Clin Experiment Res 23(5):863–869

    Article  CAS  Google Scholar 

  • Day NL, Leech SL, Richardson GA, Cornelius MD, Robles N, Larkby C (2002) Prenatal alcohol exposure predicts continued deficits in offspring size at 14 years of age. Alcohol Clin Experiment Res 26(10):1584–1591. doi:10.1097/01.ALC.0000034036.75248.D9

    Article  CAS  Google Scholar 

  • Dobbing J, Sands J (1979) Comparative aspects of the brain growth spurt. Early Hum Dev 3(1):79–83

    Article  CAS  PubMed  Google Scholar 

  • Ehrenkranz RA, Das A, Wrage LA, Poindexter BB, Higgins RD, Stoll BJ, Oh W (2011) Early nutrition mediates the influence of severity of illness on extremely LBW infants. Pediatr Res 69(6):522–529. doi:10.1203/PDR.0b013e318217f4f1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Garlick PJ (2001) Assessment of the safety of glutamine and other amino acids. J Nutr 131(9 Suppl):2556S–2561S

    CAS  PubMed  Google Scholar 

  • Hales CN, Ozanne SE (2003) For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia 46(7):1013–1019. doi:10.1007/s00125-003-1131-7

    Article  CAS  PubMed  Google Scholar 

  • Haynes TE, Li P, Li X, Shimotori K, Sato H, Flynn NE, Wang J, Knabe DA, Wu G (2009) L-Glutamine or L-alanyl-L-glutamine prevents oxidant- or endotoxin-induced death of neonatal enterocytes. Amino Acids 37(1):131–142. doi:10.1007/s00726-009-0243-x

    Article  CAS  PubMed  Google Scholar 

  • Hutchinson EA, De Luca CR, Doyle LW, Roberts G, Anderson PJ (2013) School-age outcomes of extremely preterm or extremely low birth weight children. Pediatrics 131(4):e1053–e1061. doi:10.1542/peds.2012-2311

    Article  PubMed  Google Scholar 

  • Karl PI, Kwun R, Slonim A, Fisher SE (1995) Ethanol elevates fetal serum glutamate levels in the rat. Alcohol Clin Experiment Res 19(1):177–181

    Article  CAS  Google Scholar 

  • Kwon H, Spencer TE, Bazer FW, Wu G (2003) Developmental changes of amino acids in ovine fetal fluids. Biol Reprod 68(5):1813–1820. doi:10.1095/biolreprod.102.012971

    Article  CAS  PubMed  Google Scholar 

  • Lassala A, Bazer FW, Cudd TA, Datta S, Keisler DH, Satterfield MC, Spencer TE, Wu G (2011) Parenteral administration of L-arginine enhances fetal survival and growth in sheep carrying multiple fetuses. J Nutr 141(5):849–855. doi:10.3945/jn.111.138172

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lucas JS, Inskip HM, Godfrey KM, Foreman CT, Warner JO, Gregson RK, Clough JB (2004) Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function. Am J Respir Crit Care Med 170(5):534–540. doi:10.1164/rccm.200311-1583OC

    Article  PubMed  Google Scholar 

  • Marquis SM, Leichter J, Lee M (1984) Plasma amino acids and glucose levels in the rat fetus and dam after chronic maternal alcohol consumption. Biol Neonate 46(1):36–43

    Article  CAS  PubMed  Google Scholar 

  • Mates JM, Perez-Gomez C, Nunez de Castro I, Asenjo M, Marquez J (2002a) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34(5):439–458

    Article  CAS  PubMed  Google Scholar 

  • Mates JM, Perez-Gomez C, Nunez de Castro I, Asenjo M, Marquez J (2002b) Glutamine and its relationship with intracellular redox status, oxidative stress and cell proliferation/death. Int J Biochem Cell Biol 34(5):439–458

    Article  CAS  PubMed  Google Scholar 

  • Ouellette EM, Rosett HL, Rosman NP, Weiner L (1977) Adverse effects on offspring of maternal alcohol abuse during pregnancy. N Engl J Med 297(10):528–530. doi:10.1056/NEJM197709082971003

    Article  CAS  PubMed  Google Scholar 

  • Padmanabhan R, Ibrahim A, Bener A (2002) Effect of maternal methionine pre-treatment on alcohol-induced exencephaly and axial skeletal dysmorphogenesis in mouse fetuses. Drug Alcohol Depend 65(3):263–281

    Article  CAS  PubMed  Google Scholar 

  • Poindexter BB, Ehrenkranz RA, Stoll BJ, Koch MA, Wright LL, Oh W, Papile LA, Bauer CR, Carlo WA, Donovan EF, Fanaroff AA, Korones SB, Laptook AR, Shankaran S, Stevenson DK, Tyson JE, Lemons JA (2003) Effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants. Am J Clin Nutr 77(3):737–743

    CAS  PubMed  Google Scholar 

  • Probyn ME, Zanini S, Ward LC, Bertram JF, Moritz KM (2012) A rodent model of low- to moderate-dose ethanol consumption during pregnancy: patterns of ethanol consumption and effects on fetal and offspring growth. Reprod Fertil Dev 24(6):859–870. doi:10.1071/RD11200

    Article  CAS  PubMed  Google Scholar 

  • Ramadoss J, Hogan HA, Given JC, West JR, Cudd TA (2006) Binge alcohol exposure during all three trimesters alters bone strength and growth in fetal sheep. Alcohol 38(3):185–192

    Article  CAS  PubMed  Google Scholar 

  • Ramadoss J, Wu G, Cudd TA (2008) Chronic binge ethanol-mediated acidemia reduces availability of glutamine and related amino acids in maternal plasma of pregnant sheep. Alcohol 42(8):657–666. doi:10.1016/j.alcohol.2008.08.008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rezaei R, Knabe DA, Tekwe CD, Dahanayaka S, Ficken MD, Fielder SE, Eide SJ, Lovering SL, Wu G (2013) Dietary supplementation with monosodium glutamate is safe and improves growth performance in postweaning pigs. Amino Acids 44:911–923. doi:10.1007/s00726-012-1420-x

    Article  CAS  PubMed  Google Scholar 

  • Riley EP, Infante MA, Warren KR (2011) Fetal alcohol spectrum disorders: an overview. Neuropsychol Rev 21(2):73–80. doi:10.1007/s11065-011-9166-x

    Article  PubMed Central  PubMed  Google Scholar 

  • Rosett HL, Weiner L, Lee A, Zuckerman B, Dooling E, Oppenheimer E (1983) Patterns of alcohol consumption and fetal development. Obstet Gynecol 61(5):539–546

    CAS  PubMed  Google Scholar 

  • Sawant OB, Lunde ER, Washburn SE, Chen WJ, Goodlett CR, Cudd TA (2013a) Different patterns of regional Purkinje cell loss in the cerebellar vermis as a function of the timing of prenatal ethanol exposure in an ovine model. Neurotox Teratol 35:7–13. doi:10.1016/j.ntt.2012.11.001

    Article  CAS  Google Scholar 

  • Sawant OB, Ramadoss J, Hogan HA, Washburn SE (2013b) The role of acidemia in maternal binge alcohol-induced alterations in fetal bone functional properties. Alcohol Clin Experiment Res 37(9):1476–1482. doi:10.1111/acer.12118

    Article  CAS  Google Scholar 

  • Sawant OB, Ramadoss J, Hankins GD, Wu G, Washburn SE (2014) Effects of L-glutamine supplementation on maternal and fetal hemodynamics in gestating ewes exposed to alcohol. Amino Acids 46:1981–1996. doi:10.1007/s00726-014-1751-x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schenker S, Becker HC, Randall CL, Phillips DK, Baskin GS, Henderson GI (1990) Fetal alcohol syndrome: current status of pathogenesis. Alcohol Clin Exp Res 14(5):635–647

    Article  CAS  PubMed  Google Scholar 

  • Scott MN, Taylor HG, Fristad MA, Klein N, Espy KA, Minich N, Hack M (2012) Behavior disorders in extremely preterm/extremely low birth weight children in kindergarten. J Dev Behav Pediatr 33(3):202–213. doi:10.1097/DBP.0b013e3182475287

    Article  PubMed Central  PubMed  Google Scholar 

  • Smith IE, Coles CD, Lancaster J, Fernhoff PM, Falek A (1986) The effect of volume and duration of prenatal ethanol exposure on neonatal physical and behavioral development. Neurobehav Toxicol Teratol 8(4):375–381

    CAS  PubMed  Google Scholar 

  • Spohr HL, Willms J, Steinhausen HC (1993) Prenatal alcohol exposure and long-term developmental consequences. Lancet 341(8850):907–910

    Article  CAS  PubMed  Google Scholar 

  • Streissguth AP, Martin DC, Martin JC, Barr HM (1981) The Seattle longitudinal prospective study on alcohol and pregnancy. Neurobehav Toxicol Teratol 3(2):223–233

    CAS  PubMed  Google Scholar 

  • Subramanian MG (1992) Lactation and prolactin release in foster dams suckling prenatally ethanol exposed pups. Alcohol Clin Exp Res 16(5):891–894

    Article  CAS  PubMed  Google Scholar 

  • Subramanian K, Naik VD, Sathishkumar K, Sawant OB, Washburn SE, Wu G, Yallampalli C, Saade GR, Hankins GD, Ramadoss J (2014a) Interactive effects of in vitro binge-like alcohol and ATP on umbilical endothelial nitric oxide synthase post-translational modifications and redox modulation. Reprod Toxicol 43:94–101. doi:10.1016/j.reprotox.2013.11.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Subramanian K, Naik VD, Sathishkumar K, Yallampalli C, Saade GR, Hankins GD, Ramadoss J (2014b) Chronic binge alcohol exposure during pregnancy impairs rat maternal uterine vascular function. Alcohol Clin Exp Res 38(7):1832–1838. doi:10.1111/acer.12431

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, Gorman JM (1996) Schizophrenia after prenatal famine. Further evidence. Arch Gen Psychiatry 53(1):25–31

    Article  CAS  PubMed  Google Scholar 

  • Tagare A, Chaudhari S, Kadam S, Vaidya U, Pandit A, Sayyad MG (2013) Mortality and morbidity in extremely low birth weight (ELBW) infants in a neonatal intensive care unit. Indian J Pediatr 80(1):16–20. doi:10.1007/s12098-012-0818-5

    Article  PubMed  Google Scholar 

  • van den Berg A, van Elburg RM, Westerbeek EA, van der Linde EG, Knol J, Twisk JW, Fetter WP (2007) The effect of glutamine-enriched enteral nutrition on intestinal microflora in very low birth weight infants: a randomized controlled trial. Clin Nutr 26(4):430–439. doi:10.1016/j.clnu.2007.03.002

    Article  PubMed  Google Scholar 

  • Vohr BR, Wright LL, Dusick AM, Mele L, Verter J, Steichen JJ, Simon NP, Wilson DC, Broyles S, Bauer CR, Delaney-Black V, Yolton KA, Fleisher BE, Papile LA, Kaplan MD (2000) Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994. Pediatrics 105(6):1216–1226

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Chen L, Li P, Li X, Zhou H, Wang F, Li D, Yin Y, Wu G (2008) Gene expression is altered in piglet small intestine by weaning and dietary glutamine supplementation. J Nutr 138(6):1025–1032

    CAS  PubMed  Google Scholar 

  • Wang Y, Tao YX, Cai W, Tang QY, Feng Y, Wu J (2010) Protective effect of parenteral glutamine supplementation on hepatic function in very low birth weight infants. Clin Nutr 29(3):307–311. doi:10.1016/j.clnu.2010.03.009

    Article  CAS  PubMed  Google Scholar 

  • Warren KR, Calhoun FJ, May PA, Viljoen DL, Li TK, Tanaka H, Marinicheva GS, Robinson LK, Mundle G (2001) Fetal alcohol syndrome: an international perspective. Alcohol Clin Exp Res 25 (5 Suppl): 202S–206S

  • Washburn SE, Sawant OB, Lunde ER, Wu G, Cudd TA (2013) Acute alcohol exposure, acidemia or glutamine administration impacts amino acid homeostasis in ovine maternal and fetal plasma. Amino Acids 45:543–554. doi:10.1007/s00726-012-1453-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Washburn SE, Ramadoss J, Chen WJ, Cudd TA (2014) Effects of all three trimester moderate binge alcohol exposure on the foetal hippocampal formation and olfactory bulb. Brain injury doi:10.3109/02699052.2014.947629

  • Weinberg J (1985) Effects of ethanol and maternal nutritional status on fetal development. Alcohol Clin Exp Res 9:49–55

    Article  CAS  PubMed  Google Scholar 

  • Woodall SM, Johnston BM, Breier BH, Gluckman PD (1996) Chronic maternal undernutrition in the rat leads to delayed postnatal growth and elevated blood pressure of offspring. Pediatr Res 40(3):438–443. doi:10.1203/00006450-199609000-00012

    Article  CAS  PubMed  Google Scholar 

  • Wu G (2009) Amino acids: metabolism, functions, and nutrition. Amino Acids 37(1):1–17. doi:10.1007/s00726-009-0269-0

    Article  PubMed  Google Scholar 

  • Wu G (2010) Functional amino acids in growth, reproduction, and health. Adv Nutr 1:31–37. doi:10.3945/an.110.1008

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu G (2013) Functional amino acids in nutrition and health. Amino Acids 45:407–411

    Article  CAS  PubMed  Google Scholar 

  • Wu G (2014) Dietary requirements of synthesizable amino acids by animals: a paradigm shift in protein nutrition. J Anim Sci Biotechnol 5:34

    Article  PubMed Central  PubMed  Google Scholar 

  • Wu G, Meier SA, Knabe DA (1996) Dietary glutamine supplementation prevents jejunal atrophy in weaned pigs. J Nutr 126(10):2578–2584

    CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Cudd TA, Meininger CJ, Spencer TE (2004a) Maternal nutrition and fetal development. J Nutr 134(9):2169–2172

    CAS  PubMed  Google Scholar 

  • Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004b) Glutathione metabolism and its implications for health. J Nutr 134(3):489–492

    CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Knabe DA, Li P, Li X, McKnight JR, Satterfield MC, Spencer TE (2011) Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino Acids 40(4):1053–1063. doi:10.1007/s00726-010-0715-z

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu G, Bazer FW, Dai ZL, Li DF, Wang JJ, Wu ZL (2014) Amino acid nutrition in animals: protein synthesis and beyond. Annu Rev Anim Biosci 2:387–417

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We would like to acknowledge the important role of the late Dr. Timothy Cudd in starting this study and making significant contributions. We would like to thank Emilie Lunde, Brittney Kramer, Colt Sharpton and Sudath Dahanayaka for their assistance in this study. This research was supported by NIAAA grant AA010940 and AA18166-2 (SW).

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The authors have no conflicts of interest to disclose.

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Correspondence to Shannon E. Washburn.

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Sawant, O.B., Wu, G. & Washburn, S.E. Maternal l-glutamine supplementation prevents prenatal alcohol exposure-induced fetal growth restriction in an ovine model. Amino Acids 47, 1183–1192 (2015). https://doi.org/10.1007/s00726-015-1945-x

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