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Proline metabolism in the conceptus: implications for fetal growth and development

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Abstract

Although there are published studies of proline biochemistry and nutrition in cultured cells and postnatal animals, little is known about proline metabolism and function in the conceptus (embryo/fetus, associated placental membranes, and fetal fluids). Because of the invasive nature of biochemical research on placental and fetal growth, animal models are often used to test hypotheses of biological importance. Recent evidence from studies with pigs and sheep shows that proline is a major substrate for polyamine synthesis via proline oxidase, ornithine aminotransferase, and ornithine decarboxylase in placentae. Both porcine and ovine placentae have a high capacity for proline catabolism and polyamine production. In addition, allantoic and amniotic fluids contain enzymes to convert proline into ornithine, which is delivered through the circulation to placental tissues. There is exquisite metabolic coordination among integrated pathways that support highest rates of polyamine synthesis and concentrations in placentae during early gestation when placental growth is most rapid. Interestingly, reduced placental and fetal growth are associated with reductions in placental proline transport, proline oxidase activity, and concentrations of polyamines in gestating dams with either naturally occurring or malnutrition-induced growth retardation. Conversely, increasing proline availability in maternal plasma through nutritional or pharmacological modulation in pigs and sheep enhances concentrations of proline and polyamines in placentae and fetal fluids, as well as fetal growth. These novel findings suggest an important role for proline in conceptus metabolism, growth and development, as well as a potential treatment for intrauterine growth restriction, which is a significant problem in both human medicine and animal agriculture.

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Abbreviations

IUGR:

Intrauterine growth retardation

NO:

Nitric oxide

OAT:

Ornithine aminotransferase

ODC:

Ornithine decarboxylase

POX:

Proline oxidase

References

  • Adams E, Frank L (1980) Metabolism of proline and the hydroxyprolines. Annu Rev Biochem 49:1005–1061

    Article  PubMed  CAS  Google Scholar 

  • Bazer FW (1989) Allantoic fluid: regulation of volume and composition. In: Brace RA, Ross MG, Robillard JE (eds) Reproductive and perinatal medicine: fetal and neonatal body fluids, vol 11. Perinatology Press, Ithaca, pp 135–155

    Google Scholar 

  • Bell AW, Ehrhardt RA (2002) Regulation of placental nutrient transport and implications for fetal growth. Nutr Res Rev 15:211–230

    Article  CAS  PubMed  Google Scholar 

  • Boyd CA, Lund EK (1981) L-Proline transport by brush-border membrane vesicles prepared from human placenta. J Physiol 315:9–19

    PubMed  CAS  Google Scholar 

  • Buhi WC, Ducsay CA, Bartol FF, Bazer FW, Roberts RM (1983) A function of the allantoic sac in the metabolism of uteroferrin and maternal iron by the fetal pig. Placenta 4:455–470

    PubMed  CAS  Google Scholar 

  • Caton D, Bazer FW (1978) Respiratory gases in uterine circulation of pregnant domestic swine as sampled by indwelling catheters. Am J Physiol Regul Integr Comp Physiol 234:R25–R28

    CAS  Google Scholar 

  • Caton D, Pendergast JF, Bazer FW (1983) Uterine blood flow: periodic fluctuations of its rate during pregnancy. Am J Physiol Regul Integr Comp Physiol 245:R850–R852

    CAS  Google Scholar 

  • De Onis M, Blossner M, Villar J (1998) Levels and patterns of intrauterine growth retardation in developing countries. Eur J Clin Nutr 52(Suppl 1):S5–S15

    PubMed  Google Scholar 

  • Dekaney CM, Wu G, Jaeger LA (2001) Ornithine aminotransferase messenger RNA expression and enzymatic activity in fetal porcine intestine. Pediatr Res 50:104–109

    Article  PubMed  CAS  Google Scholar 

  • Dekaney CM, Wu G, Jaeger LA (2003) Gene expression and activity of enzymes in the arginine biosynthetic pathway in porcine fetal small intestine. Pediatr Res 53:274–280

    PubMed  CAS  Google Scholar 

  • Dillon EL, Knabe DA, Wu G (1999) Lactate inhibits citrulline and arginine synthesis from proline in pig enterocytes. Am J Physiol Gastrointest Liver Physiol 276:G1079–G1086

    CAS  Google Scholar 

  • Dunlap KA, Palmarini M, Varela M, Burghardt RC, Hayashi K, Farmer JL, Spencer TE (2006) Endogenous retroviruses regulate periimplantation placental growth and differentiation. Proc Natl Acad Sci USA 103:14390–14395

    Article  PubMed  CAS  Google Scholar 

  • Finch AM, Yang LG, Nwagwu MO, Page KR, McArdle HJ, Ashworth CJ (2004) Placental transport of leucine is a porcine model of low birth weight. Reproduction 128:229–235

    Article  PubMed  CAS  Google Scholar 

  • Ford SP (1995) Control of blood flow to the gravid uterus of domestic livestock species. J Anim Sci 73:1852–1860

    PubMed  CAS  Google Scholar 

  • Friess AE, Sinowatz F, Skolek-Winnisch R, Trautner W (1980) The placenta of the pig: fine structural changes of the placental barrier during pregnancy. Anat Embryol 158:179–191

    Article  PubMed  CAS  Google Scholar 

  • Georgiades P, Ferguson-Smith AC, Burton GJ (2002) Comparative developmental anatomy of the murine and human definitive placentae. Placenta 23:3–19

    Article  PubMed  CAS  Google Scholar 

  • Hu CA, Donald SP, Yu J, Lin WW, Liu ZH, Steel G, Obie C, Valle D, Phang JM (2007) Overexpression of proline oxidase induces proline-dependent and mitochondria-mediated apoptosis. Mol Cell Biochem 295:85–92

    Article  PubMed  CAS  Google Scholar 

  • Hu CA, Lin WW, Obie C, Valle D (1999) Molecular enzymology of mammalian Δ1-pyrroline-5-carboxylate synthase—alternative splice donor utilization generates isoforms with different sensitivity to ornithine inhibition. J Biol Chem 274:6754–6762

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa T, Harada T, Koi H, Kubota T, Azuma H, Aso T (2007) Identification of arginase in human placental villi. Placenta 28:133–138

    Article  PubMed  CAS  Google Scholar 

  • Jobgen WS, Fried SK, Fu WJ, Meininger CJ, Wu G (2006) Regulatory role for the arginine-nitric oxide pathway in metabolism of energy substrates. J Nutr Biochem 17:571–588

    Article  PubMed  CAS  Google Scholar 

  • Knight JW, Bazer FW, Thatcher WW, Frank DE, Wallace HD (1977) Conceptus development in intact and unilaterally hysterectomized-ovariectomized gilts: interrelationships among hormonal status, placental development, fetal fluids and fetal growth. J Anim Sci 44:620–637

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kwon H, Wu G, Bazer FW, Spencer TE (2003b) Developmental changes in polyamine levels and synthesis in the ovine conceptus. Biol Reprod 69:1626–1634

    Article  PubMed  CAS  Google Scholar 

  • Kwon H, Ford SP, Bazer FW, Spencer TE, Nathanielsz PW, Nijland MJ, Hess BW, Wu G (2004a) Maternal undernutrition reduces concentrations of amino acids and polyamines in ovine maternal and fetal plasma and fetal fluids. Biol Reprod 71:901–908

    Article  PubMed  CAS  Google Scholar 

  • Kwon H, Wu G, Meininger CJ, Bazer FW, Spencer TE (2004b) Developmental changes in nitric oxide synthesis in the ovine placenta. Biol Reprod 70:679–686

    Article  PubMed  CAS  Google Scholar 

  • Li P, Yin YL, Li DF, Kim SW, Wu G (2007) Amino acids and immune function. Br J Nutr 98:237–252

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Borchert GL, Surazynski A, Hu CA, Phang JM (2006) Proline activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. Oncogene 25:5640–5647

    Article  PubMed  CAS  Google Scholar 

  • Mateo RD, Wu G, Bazer FW, Park JC, Shinzato I, Kim SW (2007) Dietary L-arginine supplementation enhances the reproductive performance of gilts. J Nutr 137:652–656

    PubMed  CAS  Google Scholar 

  • Murphy VE, Smith R, Giles WB, Clifton VL (2006) Endocrine regulation of human fetal growth: the role of the mother, placenta, and the fetus. Endocrine Rev 27:141–169

    Article  Google Scholar 

  • National Research Council (1985) Nutrient requirements of sheep. National Academy Press, Washington

    Google Scholar 

  • National Research Council (1998) Nutrient requirements of swine. National Academy Press, Washington

    Google Scholar 

  • Phang JM (1985) The regulatory functions of proline and pyrroline-5-carboxylic acid. Curr Top Cell Regul 25:91–132

    PubMed  CAS  Google Scholar 

  • Regnault TRH, Friedman JE, Wilkening RB, Anthony RV, Hay WW Jr (2005) Fetoplacental transport and utilization of amino acids in IUGR—a review. Placenta 26(Suppl A):S52–S62

    Article  PubMed  CAS  Google Scholar 

  • Reynolds LP, Redmer DA (2001) Angiogenesis in the placenta. Biol Reprod 64:1033–1040

    Article  PubMed  CAS  Google Scholar 

  • Ross MG, Nijland MJM (1998) Development of ingestive behavior. Am J Physiol Regul Integr Comp Physiol 274:R879–R893

    CAS  Google Scholar 

  • Sagawa N, Nishimura T, Ogawa M, Inouge A (1979) Electrogenic absorption of sugars and amino acids in the small intestine of human fetus. Membr Biochem 2:393–404

    Article  PubMed  CAS  Google Scholar 

  • Sangild PT, Schmidt M, Elnif J, Bjornvad CR, Westrom BR, Buddington RK (2002) Prenatal development of gastrointestinal function in the pig and the effects of fetal esophageal obstruction. Pediatr Res 52:416–424

    PubMed  Google Scholar 

  • Satterfield MC, Bazer FW, Spencer TE, Wu G (2007) Viagra (Sildenafil citrate) treatment enhanced fetal growth in an ovine model of intrauterine growth retardation. Pediatr Res 62:381

    Google Scholar 

  • Schmidt W (1992) The amniotic fluid compartment: the fetal habitat. Adv Anat Embryol Cell Biol 127:1–98

    PubMed  CAS  Google Scholar 

  • Schoknecht PA, Newton GR, Weise DE, Pond WG (1994) Protein restriction during pregnancy alters fetal and placental growth and allantoic fluid proteins in swine. Theriogenology 42:217–226

    Article  PubMed  CAS  Google Scholar 

  • Scholl TO, Johnson WG (2000) Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr 71(Suppl 5):1295S–1303S

    PubMed  CAS  Google Scholar 

  • Self JT, Spencer TE, Johnson GA, Hu J, Bazer FW, Wu G (2004) Glutamine synthesis in the developing porcine placenta. Biol Reprod 70:1444–1451

    Article  PubMed  CAS  Google Scholar 

  • Steel RGD, Torrie JH, Dickey DA (1997) Principles and procedures of statistics. McGraw-Hill, New York

    Google Scholar 

  • Stoll B, Henry J, Reeds PJ, Yu H, Jahoor F, Burrin DG (1998) Catabolism dominates the first-pass intestinal metabolism of dietary essential amino acids in milk protein-fed piglets. J Nutr 128:606–614

    PubMed  CAS  Google Scholar 

  • Trahair JF, Harding R (1995) Restitution of swallowing in fetal sheep restores intestinal growth after midgestation esophageal obstruction. J Pediatr Gastroenterol Nutr 20:156–161

    Article  PubMed  CAS  Google Scholar 

  • Vonnahme KA, Wilson ME, Ford SP (2001) Relationship between placental vascular endothelial growth factor expression and placental/endometrial vascularity in the pigs. Biol Reprod 64:1821–1825

    Article  PubMed  CAS  Google Scholar 

  • Wang JJ, Chen LX, Li DF, Yin YL, Wang XQ, Li P, Dangott LJ, Hu WX, Wu G (2008) Intrauterine growth restriction affects the proteomes of the small intestine, liver and skeletal muscle in newborn pigs. J Nutr 138:60–66

    PubMed  CAS  Google Scholar 

  • Wareing M, Myers JE, O’Hara M, Baker PN (2005) Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab 90:2550–2555

    Article  PubMed  CAS  Google Scholar 

  • Wu G (1996) An important role for pentose cycle in the synthesis of citrulline and proline from glutamine in porcine enterocytes. Arch Biochem Biophys 336:224–230

    Article  PubMed  CAS  Google Scholar 

  • Wu G (1997) Synthesis of citrulline and arginine from proline in enterocytes of postnatal pigs. Am J Physiol Gastrointest Liver Physiol 272:G1382–G1390

    CAS  Google Scholar 

  • Wu G (1998) Intestinal mucosal amino acid catabolism. J Nutr 128:1249–1252

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Tuo W (1995) Developmental changes of free amino acid concentrations in fetal fluids of pigs. J Nutr 125:2859–2868

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Tuo W, Flynn NE (1996) Unusual abundance of arginine and ornithine in porcine allantoic fluid. Biol Reprod 54:1261–1265

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Hu JB, Johnson GA, Spencer TE (2005) Polyamine synthesis from proline in the developing porcine placenta. Biol Reprod 72:842–850

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Cudd TA, Jobgen WS, Kim SW, Lassala A, Li P, Matis JH, Meininger CJ, Spencer TE (2007a) Pharmacokinetics and safety of arginine supplementation in animals. J Nutr 137:1673S–1680S

    PubMed  CAS  Google Scholar 

  • Wu G, Bazer FW, Davis TA, Jaeger LA, Johnson GA, Kim SW, Knabe DA, Meininger CJ, Spencer TE, Yin YL (2007b) Important roles for the arginine family of amino acids in swine nutrition and production. Livest Sci 112:8–22

    Article  Google Scholar 

  • Wu G, Bazer FW, Wallace JM, Spencer TE (2006) Intrauterine growth retardation: Implications for the animal sciences. J Anim Sci 84:2316–2337

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Davis PK, Flynn NE, Knabe DA, Davidson JT (1997) Endogenous synthesis of arginine plays an important role in maintaining arginine homeostasis in postweaning growing pigs. J Nutr 127:2342–2349

    PubMed  CAS  Google Scholar 

  • Wu G, Flynn NE, Knabe DA (2000a) Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets. Am J Physiol Endocrinol Metab 279:E395–E402

    PubMed  CAS  Google Scholar 

  • Wu G, Haynes TE, Li H, Meininger CJ (2000b) Glutamine metabolism in endothelial cells: ornithine synthesis from glutamine via pyrroline-5-carboxylate synthase. Comp Biochem Physiol A 126:115–123

    CAS  Google Scholar 

  • Wu G, Jaeger LA, Bazer FW, Rhoads JM (2004b) Arginine deficiency in preterm infants: biochemical mechanisms and nutritional implications. J Nutr Biochem 15:442–451

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Knabe DA, Flynn NE (1994) Synthesis of citrulline from glutamine in pig enterocytes. Biochem J 299:115–121

    PubMed  CAS  Google Scholar 

  • Wu G, Meininger CJ (2000) Arginine nutrition and cardiovascular function. J Nutr 130:2626–2629

    PubMed  CAS  Google Scholar 

  • Wu G, Meininger CJ (2002) Regulation of nitric oxide synthesis by dietary factors. Annu Rev Nutr 22:61–86

    Article  PubMed  CAS  Google Scholar 

  • Wu G, Morris SM (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    PubMed  CAS  Google Scholar 

  • Wu G, Pond WG, Ott T, Bazer FW (1998a) Maternal dietary protein deficiency decreases amino acid concentrations in fetal plasma and allantoic fluid of pigs. J Nutr 128:894–902

    PubMed  CAS  Google Scholar 

  • Wu G, Pond WG, Flynn SP, Ott TL, Bazer FW (1998b) Maternal dietary protein deficiency decreases nitric oxide synthase and ornithine decarboxylase activities in placenta and endometrium of pigs. J Nutr 128:2395–2402

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by National Research Initiative Competitive Grants no. 2001-35203-11247, 2003-35206-13694, 2005-35203-16252, 2006-35203-17283, 2006-35203-17199, and 2008-35206-18764 from the USDA Cooperative State Research, Education, and Extension Service, by NIH grants no. 1R21 HD049449, 5P30ES09106, and R25 CA90301, and Texas Agricultural Experiment Station (Hatch Project #82000). Our research projects with pigs and sheep were approved by Texas A&M University Animal Care and Use Committee. We thank all research personnel in our laboratories for technical assistance, Mr. Kenton Lillie for assistance with animal husbandry, and Ms. Frances Mutscher for office support.

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Authors and Affiliations

  1. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

    G. Wu, F. W. Bazer, P. Li, M. C. Satterfield & T. E. Spencer

  2. Department of Statistics, Texas A&M University, College Station, TX, 77843, USA

    S. Datta

  3. Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, 77843, USA

    G. A. Johnson

  4. Kleberg Center, Texas A&M University, 2471 TAMU, Room 212, College Station, TX, 77843-2471, USA

    G. Wu

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  1. G. Wu
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  2. F. W. Bazer
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  3. S. Datta
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  4. G. A. Johnson
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  5. P. Li
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  7. T. E. Spencer
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Correspondence to G. Wu.

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Wu, G., Bazer, F.W., Datta, S. et al. Proline metabolism in the conceptus: implications for fetal growth and development. Amino Acids 35, 691–702 (2008). https://doi.org/10.1007/s00726-008-0052-7

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  • DOI: https://doi.org/10.1007/s00726-008-0052-7

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