Intrauterine growth retardation in livestock: implications, mechanisms and solutions

51 (2008) Special Issue, 4-10
Texas A&M University, United States of America GUOYAO WU, FULLER W. BAZER, SUJAY DATTA, HAIJUN GAO, GREGORY A. JOHNSON, ARANTZATZU LASSALA, PENG LI, M. CAREY SATTERFIELD and Intrauterine growth retardation in livestock: Implications, mechanisms
Nutztier: Implikationen, Mechanismen und Lösungen) Abstract Intrauterine growth retardation (IUGR) is a significant problem in livestock production. It adversely affects neonatal survival, postnatal growth performance, efficiency of feed utilization, tissue composition (including protein, fat and minerals), meat quality, long-term health of offspring, and adult onset of disease. Genetic, epigenetic and environmental factors (including nutrition), as well as maternal maturity impact on the size and functional capacity of the placenta, placental vascular growth, uteroplacental blood flows, transfer of nutrients from mother to fetus, the endocrine milieu, as well as embryonic development of myocytes, adipocytes and other cell types. Growing evidence suggests that arginine-derived signaling molecules (nitric oxide and polyamines) play an important role in regulating these key physiological and biochemical processes. Thus, modulating arginine-metabolic pathways can enhance embryonic/fetal survival and growth, and provide a useful approach to prevent and treat IUGR. Keywords: arginine, fetal growth, livestock, placenta, postnatal growth Zusammenfassung Intrauterine Wachstumsretadierung ist ein bedeutendes Problem in der Tierproduktion mit negativen Auswirkungen auf die Lebensfähigkeit Neugeborener, postnatales Wachstum, Futterverwertung, Gewebezusammensetzung (Protein, Fett, Mineralien), Fleischbeschaffenheit und Gesundheit. Genetische, epigenetische und Umweltfaktoren sowie das Sauenalter beeinflussen die Größe und funktionelle Kapazität der Plazenta, ihre Durchblutung und den Transfer von Nährstoffen von der Mutter zum Fetus, das endokrine Milieu sowie die embryonale Entwicklung von Myozyten, Adipozyten und anderen Zellen. Arginin-abgeleitete Signalmoleküle (Stickoxide, Polyamine) spielen eine wichtige Rolle bei der Steuerung diese physiologischen und biochemischen Prozesse. Demnach kann die Modulation der Arginin-Stoffwechselwege die embryonale/fetale Überlebensrate und Wachstum verbessern und somit Ansätze zur Vermeidung und Behandlung intrauterine Wachstumsretadierung liefern. Schlüsselwörter: Arginin, fetales Wachstum, Viehbestand, Plazenta, postnatales Wachstum Introduction Litter size in mammals is a maternal trait affected by complex factors, including ovulation rate, uterine capacity, and embryonic/fetal survival (WU et al., 2006). Interestingly, heritability of litter size is low, which has been estimated to be 0.09-0.11 in pigs (URBAN et al., 1966; LUND et al., 2002) and sheep (RAO and NOTTER, 2000). Modern highly prolific sows ovulate 20 to 30 oocytes, but only deliver 9 to 15 piglets at term because of high prenatal losses (TOWN et al., 2005). The first peak of losses occurs during the peri-implantation period between days 12 and 15 of gestation. Fetal losses seem to be highest around days 35-40 of gestation, followed by mid-gestation losses from days 55 to 75, and finally the period immediately before farrowing. The highest average fetal losses at day 35 occur in large litters (>10 fetuses), suggesting a relationship between the uterine capacity and fetal mortality (TOWN et al., 2005). The greatest restraint on litter size in pigs is placental development and function in early gestation and uterine capacity at all periods of gestation, rather than simply the number of ovulations or embryos (BAZER et al., 1988). Because heritability for the number of piglets born alive is low (0.06-0.09; HALEY and LEE, 1992; LUND et al., 2002), improvement in litter size through animal breeding has been slow. Indeed, in the U.S., litter size in swine increased at the rate of 0.052 pigs/year between 1980 and 2000 (JOHNSON, 2000). Among domestic animals, pigs exhibit the most severe naturally occurring IUGR (WU et al., 2006). Before day 35 of gestation, porcine embryos are uniformly distributed within each uterine horn. After this time in gestation, uterine capacity becomes a limiting factor for fetal growth even though fetuses are distributed relatively uniformly (BAZER et al., 1988). At birth, runt piglets may weigh only one-half or even one-third as much as the largest littermates, and key organs involved in nutrient digestion and utilization in runt pigs are disproportionately smaller than those of the larger littermates (WU et al., 2006). Placental insufficiency is a major factor contributing to low birth-weights of piglets. IUGR has permanent negative impacts on neonatal adjustment, preweaning survival, postnatal growth, feed utilization efficiency, lifetime health, tissue composition (including protein, fat and minerals), meat quality, as well as reproductive and athletic performance (WU et al., 2006). Because IUGR remains a significant problem in mammals as indicated for pigs (Table 1), increasing embryonic/ fetal survival, growth, and development is of enormous importance for optimizing livestock production. Table 1 Litter size and birth weights of pigs Number of piglets born alive per litter, n Number of piglets born dead per litter, n Average birth weight of all piglets born, kg Average birth weight of piglets born alive, kg at various ranges of birth weights Data are means ± SEM. Gilts (Yorkshire × Landrace dams and Duroc × Hampshire sires) were bred at ~8 months of age and fed daily a 2-kg diet (WU et al., 2005). Data were analyzed by ANOVA or Chi-square for randomized complete block design (MATEO et al., 2007). *P<0.05 vs piglets born in Spring; 1Piglets were born between March 22 and April 5 in 2003-2007; 2Piglets were born between October 25 and November 7 in 2003-2007 Role of placental growth in embryonic/fetal development The functional capacity of the placenta must be adequate for normal development of the fetus. Immediately after implantation of the conceptus, various genes are expressed to initiate placental formation (VONNAHME and FORD, 2004). Remarkably, the placenta undergoes rapid formation of new blood vessels (angiogenesis) and marked growth during pregnancy (REYNOLDS and REDMER, 2001). The pig possesses a noninvasive, diffuse type of epitheliochorial placentation, and its placenta grows rapidly between Days 20 and 60 of gestation and its development is maximal by Day 70 of gestation (BAZER et al., 1988). Placental angiogenesis is necessary to increase placental-fetal blood flow and, thus, the supply of nutrients from mother to fetus. Notably, the Meishan pig, which has 3 to 5 more piglets per litter than US or European pig breeds, exhibits more vascularization in the placenta (VONNAHME and FORD, 2004), enabling the Meishan fetus to obtain sufficient nutrients from a relatively small placenta (BAZER et al., 1988). Insufficient placental vascularization may lead to a progressive deterioration in placental function and a decrease in placental transfer of oxygen and nutrients to the fetus (WU et al., 2006). Thus, understanding the mechanisms that regulate placental growth is crucial for improving and controlling the survival, growth and development of fetal pigs. Role of NO and polyamines in placental growth Besides insulin-like growth factors and vascular endothelial growth factors, nitric oxide (NO) and polyamines (putrescine, spermidine, and spermine), which are all products of arginine catabolism, also play crucial roles in angiogenesis, embryogenesis, placental trophoblast growth, uteroplacental blood flow, as well as fetal growth and development in the uterus (WU et al., 2006). Consistent with this notion, we recently discovered unusually high concentrations of arginine in porcine allantoic fluid during early gestation. Particularly, arginine plus ornithine account for 50 % and 55 % of the total allantoic fluid α-amino acid nitrogen on Days 40 and 45 of gestation, respectively. Concentrations of arginine and ornithine in allantoic fluids on Day 60 of gestation are lower than on Days 35 to 45 of gestation, but remain the greatest among all amino acids. The arginine family of amino acids is also highly abundant in ovine conceptus (e.g., 10 mM citrulline and 25 mM glutamine at Day 60). These novel and intriguing observations have raised important questions regarding the role of arginine in growth and development of the conceptus. In support of this notion, rates of NO and polyamine synthesis in both porcine and ovine placentae are highest during early gestation when placental growth is most rapid (KWON et al., 2004; WU et al., 2005; WU et al., 2006). Therefore, we proposed that impaired placental growth (including vascular growth) or function, possibly owing to reduced placental synthesis of NO and polyamines may contribute primarily to IUGR in response to both maternal undernutrition and overnutrition (WU et al., 2006). Myocytes and adipocytes are derived from a common mesenchymal precursor. Therefore, excessive amounts of adipose tissue are developed at the expense of skeletal muscle when embryonic myogenesis is impaired (KABLAR et al., 2003). There are two developing muscle fibers in fetal pigs: primary fibers (formed by the rapid fusion of primary myoblasts between Days 25 and 50 of gestation) and secondary fibers (formed on the surface of primary fiber between approximately Days 50 and 90 of gestation). The numbers of secondary muscle fibers, but not primary muscle fibers, are affected by conditions in utero (DWYER et al., 1994). The total number of muscle fibers is fixed at birth and is a major factor affecting growth of skeletal muscle and, therefore, the postnatal growth of animals (NISSEN et al., 2003). The differences in prenatal and postnatal growth rates are related to a lower ratio of secondary to primary muscle fibers and a smaller size of the fibers (HANDEL and STICKLAND, 1987). Abnormal regulation of intracellular protein turnover, adipogenesis, and mitochondrial biogenesis is likely a major factor responsible for reduced protein deposition in skeletal muscle and increased fat accretion in IUGR fetuses and offspring. In this regard, it is noteworthy that recent results of proteomics studies indicate that the abundance of proteasome is greater in skeletal muscle and liver, whereas levels of eukaryotic translation initiation factor 3 are lower in skeletal muscle of IUGR piglets at birth, compared with piglets with normal birth weights (WANG et al., 2007). Polyamines are necessary for both proliferation and differentiation of cells and likely mediate growth and development of fetal muscle fibers and adipocytes. In support of this view, we noted that concentrations of arginine, ornithine, and polyamines were reduced by 28 to 35 % in skeletal muscle of IUGR fetal pigs compared to those in average-weight littermates. Similarly, concentrations of arginine, putrescine and spermidine were 26 to 32 % lower in gastrocnemius muscle of IUGR fetal lambs in response to maternal undernutrition. Further, physiological levels of NO inhibit growth of adipocytes (JOBGEN et al., 2006). Because adipose tissue of fetal lambs in underfed ewes has 33 % lower levels of constitutive NO synthase activity, decreased NO availability is expected to facilitate growth of preadipocytes in IUGR lambs. In addition to NO and polyamines, arginine and other functional amino acids (e.g. glutamine, leucine and proline) may also regulate placental growth as well as embryonic/fetal survival, growth and development via the signaling mechanism of mammalian target of rapamycin (mTOR, now known as FKBP12-Rapamycin Complex-Associated Protein 1 or FRAP1; WU et al., 2006). Environmental insults during a critical period of fetal development during gestation may have a permanent effect on progeny throughout postnatal life. This phenomenon is termed fetal programming, which may result from alterations in the epigenetic state of the fetal genome and expression of imprinted genes (WU et al., 2006). Epigenetic alterations (stable alterations of gene expression through covalent modifications of DNA and core histones) in early embryos may be carried forward to subsequent developmental stages (WATERLAND and JIRTLE, 2004). Two mechanisms mediating epigenetic effects are DNA methylation (occurring in 5’-positions of cytosine residues within CpG dinucleotides throughout the mammalian genome) and histone modification (acetylation and methylation). Methylation of CpG can regulate gene expression by modulating binding of methyl-sensitive DNA-binding proteins, thereby affecting regional chromatin conformation (OOMMEN et al., 2005). Histone acetylation or methylation can alter positioning of histone-DNA interactions and the affinity of histone binding to DNA, thereby affecting gene expression (WATERLAND and JIRTLE, 2004). Notably, DNA and protein methylation are catalyzed by specific DNA and protein methyltransferases with S-adenosylmethionine as the methyl donor. In addition to methionine, one-carbon unit metabolism, which is also affected by serine, glycine, histidine, choline, and B vitamins (including folate, vitamin B12 and vitamin B6), may provide a molecular mechanism for the impact of maternal nutrition on fetal programming for postnatal growth performance and disease susceptibility (WU et al., 2006). Improvement of pregnancy outcome via modulation of the arginine-NO pathway The naturally occurring inability of placentae to supply an adequate amount of nutrients to fetuses in pigs is exacerbated further by the current widespread practice in the swine industry of restricted feeding programs to prevent excessive weight gain of gilts and sows during pregnancy. Although such a feeding regimen can ameliorate farrowing difficulties and appetite reduction during lactation, gilts and sows may not receive sufficient amounts of dietary arginine during early- to late-gestation for supporting optimal embryonic/fetal survival and growth. Remarkably, dietary supplementation with 1.0 % arginine-HCl between Days 30 and 114 of gestation increased concentrations of arginine and ornithine in plasma by 77 % and 53 %, respectively (MATEO et al., 2007). The arginine treatment did not adversely affect body weight or backfat thickness of gilts, but increased the number of live-born piglets by 2 and litter birth-weight by 24 % (MATEO et al., 2007). These findings provide the first evidence for improved pregnancy outcome in pigs through dietary arginine supplementation. A relative placental deficiency also results in IUGR in litter-bearing sheep (WU et al., 2006). Thus, through an increase in concentrations of cGMP (which mediates the action of NO on blood vessels) and thus uteroplacental blood flow, intramuscular administration of Viagra (3 x 50 mg per day) to ewes receiving 100 % or 50 % of NRC nutrient requirements between Days 28 to 112 of gestation enhanced fetal growth by 20 to 25 % (SATTERFIELD et al., 2007). In addition, intravenous infusion of arginine to underfed ewes (50 % of NRC nutrient requirements) between Days 60 and 147 of pregnancy (27 mg/kg body wt, three times per day) prevented fetal growth restriction (our unpublished data). Furthermore, arginine supplementation to prolific ewes (4-7 fetuses/dam) enhanced fetal development and survival, as well as birth weight (our unpublished data). An increase in the numbers of live-born pigs and lambs will markedly reduce production costs associated with reproduction and lactation in dams, whereas an increase in the vitality of neonates will increase their survival to weaning (WU et al., 2006). At present, little is known about effects of arginine treatment on conception rate or early embryo survival in any species. Nonetheless, recent findings provide a compelling basis for future studies to define the underlying mechanisms for the beneficial effect of dietary arginine supplementation on embryonic and fetal development. Because long-term oral or intravenous administration of arginine is safe for livestock species (WU et al., 2007), the use of arginine holds great promise in the prevention and treatment of IUGR, as well as improvements of postnatal growth performance and health. Acknowledgments This work was supported by National Research Initiative Competitive Grants no. 2001-35203-11247, 2003-35206-13694, 2005-35203-16252, 2006-35203-17283 and 2006-35203-17199 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). References BAZER, F.W.; THATCHER, W.W.; MARTINAT-BOTTE, F.; TERQUI, M.: Conceptus development in Large White and prolific Chinese Meishan pigs. J. Reprod. Fert. 84 (1988),
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Corresponding author: GUOYAO WU Texas A&M University College Station TX 77843 USA email:


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