J. Anim Sci. 2008. 86:820-826. doi:10.2527/jas.2007-0624
© 2008 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Baggs ewes adapt to maternal undernutrition and maintain conceptus growth by maintaining fetal plasma concentrations of amino acids1
W. S. Jobgen*,
S. P. Ford
,
S. C. Jobgen*,
C. P. Feng*,
,
B. W. Hess,
P. W. Nathanielsz
,
P. Li* and
G. Wu*,2
* Department of Animal Science and Faculty of Nutrition, Texas A&M University, College Station 77843;
and
Department of Animal Science and Center for the Study of Fetal Programming, University of Wyoming, Laramie 82071;
and
Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China 100029; and and
Department of Obstetrics and Gynecology, University of Texas Health Sciences Center, San Antonio 78299
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Abstract
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Adequate delivery of AA is essential for normal fetal growth and development. Recently, we reported that when ewes from the University of Wyoming flock (farm flock with adequate nutrition) were fed 50% (nutrient-restricted) or 100% (control-fed) of the NRC-recommended nutrient requirements between d 28 and 78 of gestation, fetal weights as well as concentrations of most AA in maternal and fetal blood were substantially reduced in nutrient-restricted vs. control-fed pregnancies. The current study utilized Baggs ewes, which were selected under a markedly different production system (range flock with limited nutrition), to test the hypothesis that adaptation of ewes to nutritional and environmental changes may alter placental efficiency and conceptus nutrient availability in the face of maternal nutrient restriction. Baggs ewes received 50 or 100% of the NRC nutrient requirements between d 28 and 78 of pregnancy. On d 78, maternal uterine arterial and fetal umbilical venous blood samples were obtained, and the ewes were euthanized. Amino acids and their metabolites (ammonia, urea, and polyamines) in plasma were analyzed using enzymatic and HPLC methods. The results showed that maternal plasma concentrations of 9 AA (Asp, Ile, Leu, Lys, Orn, Phe, Thr, Trp, and Val) as well as maternal and fetal plasma concentrations of ammonia and urea were reduced (P < 0.05) in nutrient-restricted compared with control-fed Baggs ewes. However, fetal plasma concentrations of all AA and polyamines did not differ (P = 0.842) between the 2 groups of ewes. Collectively, these findings suggest that Baggs ewes, by adapting to the harsh conditions and limited nutrition under which they were selected, were able to maintain fetal concentrations of AA in the face of a maternal nutrient restriction through augmenting placental efficiency.
Key Words: fetal growth • fetal programming • fetal intrauterine growth restriction • nutrition • pregnancy
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INTRODUCTION
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Unsupplemented pregnant ewes on rangeland pastures often experience prolonged bouts of less than 50% of NRC-recommended nutrient requirements, which results in fetal intrauterine growth restriction (Thomas and Kott, 1995
; Redmer et al., 2004). Amino acids are major maternal substrates sustaining fetal growth and development in mammals, including sheep (Bell et al., 1987; Wu et al., 2004). In an initial study to determine the effect of early to midgestation nutrient restriction on the ovine conceptus (embryo/fetus and extraembryonic placental membranes), we utilized a flock of Western white-face ewes that were maintained as a farm flock by the University of Wyoming (UW; Vonnahme et al., 2003, 2006). These sheep had adapted to a sedentary lifestyle and were fed a diet that met or exceeded NRC-recommended nutrient requirements (NRC, 1985). We reported that maternal nutrient restriction (50% of the NRC requirements) between d 28 and 78 of gestation in UW ewes reduced concentrations of most AA in maternal and fetal plasma (Kwon et al., 2004a), as well as reduced fetal growth (Vonnahme et al., 2003, 2006).
Adaptation of ewes to environmental changes may alter placental transport of nutrients, maternal and fetal metabolism, and pregnancy outcomes (Reynolds et al., 2006). The current study was conducted with another flock of ewes of similar breeding, age, size, and BCS to UW ewes but was maintained under a different environment and management system. This range flock was located near Baggs, Wyoming (Baggs ewes) and was well-adapted to a nomadic existence and a subsistence diet throughout the year. Vonnahme et al. (2006) reported that maternal undernutrition between d 28 and 78 of gestation did not affect fetal plasma concentrations of glucose or fetal growth in Baggs ewes. Thus, it is important to determine whether AA concentrations in fetal plasma may be affected in underfed Baggs ewes.
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MATERIALS AND METHODS
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Animals and Diets
All animal procedures were approved by the UW Animal Care and Use Committee.
Multiparous, Western white-face ewes of similar breeding, age, size, and parity to the UW ewes utilized in our previously published study (Vonnahme et al., 2006) were obtained from a range flock operation located near Baggs, Wyoming (Baggs ewes). Baggs ewes were adapted over approximately 30 yr to a nomadic existence, traveling approximately 402 km/yr to graze a land mass that ranges from desert terrain to high mountain pastures with limited nutritional supplementation.
Baggs ewes were maintained at the UW animal facilities for 1 mo before breeding, which began on September 1, 2004. Animals were fed alfalfa hay at 2% of BW from 30 d before mating to d 20 postmating. The alfalfa hay was analyzed for nutrients (Hess et al., 1996) and contained 92.3% DM, including 10.4% ash, 42.1% NDF, 29.4% ADF, 15.3% CP, and 67.6% IVDMD (all as % of DM). All ewes were checked for estrus twice daily at 0700 and 1600 with a single fertile ram of similar breeding at first exhibition of estrus and 12 h later (first day of mating = d 0). The experimental diet consisted of a pelleted beet pulp (79.7% TDN, 10% CP, and 12.09 MJ of ME/kg; DM basis) and a mineral-vitamin mixture (Vonnahme et al., 2003). Amounts of daily dietary intake per metabolic BW (BW0.75) were calculated on a DM basis to meet the NRC (1985)-recommended total TDN required for maintenance of an early pregnant ewe. On d 21 of gestation, all ewes were placed in individual pens and fed 100% of the NRC nutrient requirements (control diet). On d 28, ewes with singleton pregnancies, as identified using ultrasonography (Ausonics Microimager 1000 sector scanning instrument, Ausonics Pty Ltd., Sydney, Australia), were randomly assigned to remain on the control diet (control-fed; 100% of the NRC nutrient requirements for the early-pregnant ewe) or were fed the control ration at 50% of the NRC-recommended nutrient requirements (nutrient-restricted) through d 78. There were 6 ewes per treatment group. Beginning on d 28 of gestation, and continuing at 7-d intervals throughout the study, ewes were weighed, and dietary intakes were adjusted for BW changes.
We used 6 ewes per treatment group on the basis of power calculation (Ostle, 1963) and variation of plasma metabolites in Baggs ewes (Vonnahme et al., 2006), as follows. Consider testing H:µ1 = µ2 vs. A:µ1 
µ2 at 5% significance level. If SD for maternal glucose concentrations = 6.4 mg/dL (Vonnahme et al., 2006) and a difference 
= |µ1 – µ2 | = 13.5 mg/dL was to be detected with a probability of 0.9, D = /SD = 13.5/6.4 = 2.1. From appendix 10 in Ostle (1963), we then obtained n = 6 for the number of animals required per treatment group.
Blood Sampling and Tissue Collection
On d 78 of gestation, ewes were sedated with ketamine (13 mg/kg of BW), and anesthesia was maintained with 1 to 2% isoflurane inhalation. After the tip of the gravid uterine horn was exposed, uterine arterial and umbilical venous blood samples were collected into chilled heparinized vacutainer tubes (sodium heparin, 143 USP units, Becton Dickinson, Franklin Lakes, NJ), centrifuged, and the plasma was stored at –80°C. Ewes were euthanized through administration of an overdose of sodium pentobarbitol (Abbott Laboratories, Abbott Park, IL) and exsanguinated (Vonnahme et al., 2006).
Analyses of Plasma AA, Polyamines, Ammonia, and Urea
Amino acids and polyamines were analyzed using HPLC methods (Wu et al., 1997, 1998; Kwon et al., 2003b). Amino acids and polyamines in samples were quantified on the basis of authentic standards (Sigma Chemicals, St. Louis, MO) using Millenium-32 Software (Waters Inc., Milford, MA). Ammonia and urea were analyzed enzymatically using Glu dehydrogenase and urease plus Glu dehydrogenase, respectively (Wu, 1995).
Statistical Analysis
Dietary intake of nutrients (50% vs. 100% of the NRC requirements) by pregnant ewes with singleton pregnancies was considered as the only treatment factor. Thus, 1-way ANOVA was used to analyze the maternal data. A separate analysis was performed for the fetal data. To compare the ewe vs. fetus observations, a third set of response data was created, in which the difference in plasma AA between an individual ewe and its fetus was generated for each dam, and this difference was analyzed using 1-way ANOVA. All statistical analyses were performed using the SAS for Windows (SAS Inst. Inc., Cary, NC). Probability values <0.05 were taken to indicate statistical significance.
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RESULTS
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Plasma Concentrations of Polyamines, Ammonia, and Urea
Concentrations of polyamines were lower (P < 0.05) in maternal plasma than in fetal plasma at d 78 of gestation (Table 1). Maternal nutrient restriction reduced (P < 0.05) concentrations of polyamines in maternal plasma, whereas fetal plasma concentrations did not differ (P > 0.05) between control-fed and nutrient-restricted Baggs ewes. Maternal nutrient restriction decreased maternal and fetal plasma concentrations of both ammonia and urea in Baggs ewes.
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Table 1. Concentrations of polyamines, ammonia, and urea in maternal and etal plasma from Baggs ewes on d 78 of gestation1
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Fetal:Maternal Ratios for Plasma Concentrations of Polyamines, Ammonia, and Urea
Ratios of fetal to maternal concentrations of polyamines were much greater (P < 0.05) than 1.0 in both control-fed and nutrient-restricted Baggs ewes at d 78 of gestation (Table 2). The values were approximately 1 for ammonia and urea (Table 2). Maternal undernutrition increased (P < 0.05) the fetal:maternal ratio for polyamines by 24% but did not affect fetal:maternal ratios for ammonia or urea (Table 2).
Plasma Concentrations of AA
Concentrations of 9 AA (Asp, Ile, Leu, Lys, Orn, Phe, Thr, Trp, and Val) were reduced (P < 0.05) in the maternal plasma of nutrient-restricted compared with control-fed Baggs ewes. Nutrient restriction decreased (P < 0.05) maternal plasma concentrations of total 
-AA by 5.5%. Interestingly, fetal plasma concentrations of each of the measured AA or total AA did not differ between control-fed and nutrient-restricted Baggs ewes. Except for Cys and His, concentrations of all other AA were much greater (P < 0.05) in fetal plasma than in maternal plasma of either control-fed or nutrient-restricted ewes (Table 3).
Fetal:Maternal Ratios for Plasma AA
β-Alanine exhibited the greatest ratio of fetal:maternal plasma concentrations (approximately 14), followed by Ser and Thr in Baggs ewes (Table 4). Ratios of fetal to maternal plasma concentrations for most AA did not differ (P < 0.05) between control-fed and nutrient-restricted ewes (Table 4). These unaltered AA were Ala, -Ala, Arg, Asp, citrulline, Cys, Gln, Glu, Gly, His, Met, Pro, Ser, taurine, and Tyr. Notably, ratios of fetal:maternal plasma concentrations for Asn, Ile, Leu, Lys, Orn, Phe, Thr, Trp, and Val were much greater (P < 0.05) in nutrient-restricted ewes than in control-fed ewes (Table 4).
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DISCUSSION
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Maternal nutrient restriction reduces the availabilities of AA in the conceptus of UW ewes that were previously raised under adequate nutrition conditions before conception (Kwon et al., 2004a). Amino acids are major fuels for the ovine fetus (Bell et al., 1987; Kwon et al., 2003a). In addition to serving as building blocks for tissue proteins, AA are potent antioxidants, regulators of hormone secretion, and cell-signaling molecules (Shi et al., 2004; Jobgen et al., 2006). Furthermore, AA (including nutritionally essential AA) are precursors for the synthesis of nonprotein substances with biological importance, including NO, polyamines, neurotransmitters, amino sugars, purine and pyrimidine nucleotides, creatine, carnitine, porphyrins, melatonin, melanin, phospholipids, and sphingolipids (Wu and Self, 2005; Li et al., 2007). Nitric oxide, a product of Arg catabolism (Wu and Morris, 1998), plays a crucial role in regulating placental angiogenesis and fetal-placental blood flows during gestation (Reynolds and Redmer, 2001; Kwon et al., 2004b; Reynolds et al., 2005b). Polyamines (polycationic molecules) regulate gene expression, signal transduction, ion channel function, DNA and protein synthesis, as well as cell proliferation, differentiation, and function (Flynn et al., 2002). Thus, reduced availability of AA in the conceptus plays a major nutritional role in fetal growth restriction in nutrient-restricted ewes (Kwon et al., 2004a). Although some AA can be synthesized in mammals, the rates of their synthesis may not meet the requirements for optimal growth, reproduction, and health under certain conditions. These AA are now termed conditionally essential AA or functional AA in animal nutrition (Wu and Self, 2005; Wu and Kim, 2007).
Developmental adaptations to altered maternal nutrition, which provide a mechanism for ensuring fetal survival, may permanently change the structure, physiology, and metabolism of the offspring (Barker and Clark, 1997). Thus, there is growing interest in the effect of maternal nutrition on production performance in livestock (Redmer et al., 2004; Reynolds et al., 2005a; Wu et al., 2006). Baggs ewes had previously been selected for mountain-grazing under a harsh environment and variable nutritional input during their life cycle (from the embryonic development to postnatal growth and to adulthood; Vonnahme et al., 2006). Recent studies show that, in contrast to intensively managed UW ewes, fetal growth was not reduced in extensively managed Baggs ewes in response to severe maternal nutrient restriction (Vonnahme et al., 2003, 2006). Therefore, Baggs sheep are a unique model for testing the hypothesis that the adaptation of ewes to environmental changes (including diets) may affect placental efficiency and nutrient availability in the conceptus. Determination of changes in maternal and fetal plasma concentrations of AA in control-fed and nutrient-restricted Baggs ewes aids in providing information on the nature of this pregnancy adaptation.
Concentrations of AA in fetal plasma are affected by many factors, including intracellular protein turnover, AA synthesis, and AA degradation in fetal tissues, as well as placental transfer of AA (Wu et al., 2004; Bell et al., 2005). A reduction in maternal and fetal oxidation of AA may be crucial for minimizing their irreversible loss in dams and conceptuses under conditions of severe maternal nutrient restriction. This mechanism was active in both UW ewes (Kwon et al., 2004a) and Baggs ewes (the current study), as indicated by the reduced concentrations of ammonia and urea in their maternal and fetal plasma in response to nutrient restriction. Interestingly, UW ewes underfed between early and midgestation exhibited substantial decreases in maternal plasma concentrations of 17 AA [including all essential AA except for His (Kwon et al., 2004a)]. In contrast, maternal plasma concentrations of 2 nonessential AA (Asp and Orn) and 7 essential AA (Ile, Leu, Lys, Phe, Thr, Trp, and Val) were reduced in nutrient-restricted Baggs ewes, compared with control-fed dams. These results indicate that, under severe conditions of nutrient restriction, neither UW nor Baggs ewes were able to maintain maternal homeostasis of the majority of essential AA, but Baggs ewes were more capable of regulating the maternal homeostasis of most nonessential AA than UW ewes. The underlying mechanisms are likely complex and may involve 1) insufficient syntheses of AA by ruminal microbes due to the reduced intake of DM and 2) altered metabolism of AA in mammalian tissues; including the small intestine, liver, and skeletal muscle (Wu, 1998; Wu et al., 2004; Bell et al., 2005).
Maternal nutrient restriction during early to midgestation exerted a different effect on fetal plasma concentrations of AA in Baggs ewes (Table 3
) than in UW ewes (Kwon et al., 2004a). In underfed UW ewes, a reduction in maternal plasma levels of most AA was associated with a reduction in their fetal plasma concentrations (Kwon et al., 2004a). However, this phenomenon was not observed in underfed Baggs ewes. Indeed, although maternal plasma concentrations of 7 neutral AA (Asp, Ile, Leu, Phe, Thr, Trp, and Val) and 2 basic AA (Lys and Orn) were reduced in nutrient-restricted Baggs ewes compared with control-fed dams, fetal plasma concentrations of these and other AA did not differ between the 2 groups of Baggs ewes. Because fetal growth and therefore the amounts of AA used for fetal protein deposition were similar between control-fed and nutrient-restricted Baggs ewes, we suggest that an increase in the placental transfer of AA from mother to fetus may be partly responsible for maintenance of fetal AA homeostasis in underfed Baggs ewes. Similarly, increases in the placental transport of polyamines and their fetal synthesis may help maintain their homeostasis and supporting fetal growth in underfed Baggs ewes. Maintenance of the fetal homeostasis of AA is likely a major mechanism for sustaining normal fetal growth in underfed Baggs ewes.
Several AA transporters have been identified in the ovine placenta (Regnault et al., 2005). They include system A (for neutral AA), system ASC (for Ala, Ser, and Cys), system Bo (for neutral AA and with broad specificity), system bo,+ (for neutral and cationic AA), system L (for large hydrophobic neutral AA), system y+L (for cationic and neutral AA), system y+ (cationic AA), system XAG (for anionic AA), and system TAU (for taurine). Available evidence indicates a downregulation of placental systems A, L, y+, and XAG in the studied species (including sheep) under conditions associated with fetal growth restriction (Regnault et al., 2005; Jones et al., 2007). These findings are consistent with reduced concentrations of most AA in fetal plasma of UW ewes (Kwon et al., 2004a). Whether expression of placental AA transporters is altered in Baggs ewes remains to be defined.
Although ovine placental growth is complete by mid-gestation (Mellor, 1983; Ehrhardt and Bell, 1995), individual placentomes can undergo morphologic and functional transformations as fetal demand for nutrients increases in the second half of gestation (Ford, 1995; Osgerby et al., 2004). The gross morphology of ovine placentomes alters under adverse intrauterine conditions, which may influence placental nutrient transfer (Ward et al., 2006). Results from several laboratories demonstrate an increased conversion of type A placentomes to B, C, and D placentomal types in response to maternal undernutrition (Hoet and Hanson, 1999; Osgerby et al., 2002, 2004). We have reported that as placentomes progress from type A through types B, C, and D, they increase in size and vascularity (Ford et al., 2004) as well as blood flow per gram of tissue (Ford et al., 2006). On d 78 of pregnancy, both control-fed and nutrient-restricted UW ewes exhibited predominantly A-type placentomes, whereas Baggs ewes exhibited fewer type A and more type B, C, and D placentomes compared with UW ewes (Vonnahme et al., 2006). Consistent with this notion, we found that fetal plasma concentrations of total AA were 60 and 76% greater in Baggs ewes (Table 3) than in UW ewes (Kwon et al., 2004a) under control-fed and nutrient-restricted conditions, respectively. Additionally, placental efficiency (indicated by a fetal:placental weight ratio) was increased in nutrient-restricted Baggs ewes in association with an increased conversion of type A to more efficient types B, C, and D placentomes (Ford et al., 2004; Vonnahme et al., 2006). Therefore, in underfed Baggs ewes, the favorable microvascular structure of the placentomes would be expected to increase the delivery of nutrients and oxygen from mother to fetus. Future studies are necessary to determine expression of genes related to placental angiogenesis (Spencer et al., 2008), as well as utero-placental blood flows in control and underfed Baggs ewes.
In conclusion, Baggs ewes, which were adapted to reproduce and grow under the harsh mountain extensive grazing production system in Wyoming, did not exhibit alterations in fetal concentrations of AA or intrauterine growth restriction in response to a 50% reduction in maternal nutrient intake. These results are in contrast to those for UW ewes that had previously been well-fed under a different management system (Kwon et al., 2004a). Our findings suggest that Baggs ewes adapted to nutrient restriction by favorably modifying their placentomal structures and increasing placental transfer of nutrients to the fetus.
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Footnotes
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1 Supported by National Research Initiative Competitive Grants 2001-35203-11247 and 2005-35203-16252, National Institutes of Health grants R21 HD049449-01A2 and HD 21350, University of Wyoming BRIN P20 and RR16474, and INBRE P20 RR016474-04. We thank Thomas E. Spencer for your helpful discussion, Jason Sawyer for advice on statistical analysis, and Frances Mutscher for office support (all at Texas A&M University). 
2 Corresponding author: g-wu{at}tamu.edu
Received for publication October 2, 2007.
Accepted for publication December 14, 2007.
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C. F. Rueda-Clausen, J. S. Morton, and S. T. Davidge
Effects of hypoxia-induced intrauterine growth restriction on cardiopulmonary structure and function during adulthood
Cardiovasc Res,
March 1, 2009;
81(4):
713 - 722.
[Abstract]
[Full Text]
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S. T. Davidge, J. S. Morton, and C. F. Rueda-Clausen
Oxygen and Perinatal Origins of Adulthood Diseases: Is Oxidative Stress the Unifying Element?
Hypertension,
November 1, 2008;
52(5):
808 - 810.
[Full Text]
[PDF]
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Abstract
INTRODUCTION
