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© 2008 American Society for Nutrition J. Nutr. 138:1421-1425, August 2008

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Dietary Arginine Supplementation during Early Pregnancy Enhances Embryonic Survival in Rats1,2

Xiangfang Zeng3, Fenglai Wang3,*, Xia Fan4, Wenjun Yang3, Bo Zhou5, Pengfei Li3, Yulong Yin6, Guoyao Wu3,7 and Junjun Wang3,*

3 State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China 100094; 4 Institute of Quality and Standards for Agri-product, Chinese Academy of Agricultural Sciences, Beijing, China 100081; 5 Dr. Bob Zhou Intech Bio-Chem., Co. Ltd, Shenzhen, China 518020; 6 Institute of Subtropical Agriculture, The Chinese Academy of Sciences, Changsha, Hunan, China 410128; and 7 Department of Animal Science, Texas A&M University, College Station, TX 77843

* To whom correspondence should be addressed. E-mail: wangfl{at}cau.edu.cn or jkywjj{at}hotmail.com.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Four experiments were conducted with 120 pregnant Sprague-Dawley rats to determine effects of dietary arginine supplementation on embryonic survival. Rats were fed a nonpurified diet supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) throughout pregnancy (Expt. 1), between d 1 and 7 of gestation and then the nonpurified diet until parturition (Expt. 2), between d 1 and 7 of gestation for determining the number of surviving embryos on d 7 (Expt. 3), or between d 1 and 4 of pregnancy for blood sampling on d 5 after overnight food deprivation (Expt. 4). Litter size increased (P < 0.01) in response to arginine supplementation throughout pregnancy (14.5 ± 0.62 vs. 11.3 ± 0.61) or during the first 7 d of pregnancy (14.7 ± 0.33 vs. 11.3 ± 0.37). The number of surviving embryos was greater (P < 0.01) when arginine was supplemented between d 1 and 7 of pregnancy (14.7 ± 0.39 vs. 11.4 ± 0.66). Concentrations of nitric-oxide metabolites, arginine, proline, glutamine, and ornithine were higher (P < 0.05), but urea levels were lower (P < 0.05) in the serum of arginine-supplemented rats compared with the control group. The arginine treatment increased (P < 0.05) protein levels for inducible and constitutive nitric-oxide synthase at implantation sites by 35–37%. These results indicate that dietary arginine supplementation enhances embryonic survival, therefore increasing litter size by 30% at term birth. This novel finding has important implications for preventing early pregnancy loss and enhancing reproductive performance in mammals.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Arginine is a conditionally essential amino acid for many mammals, including rats (1,2). Arginine serves as an essential precursor for the synthesis of biologically important molecules, such as ornithine, proline, polyamines, creatine, and nitric oxide (3). In addition, arginine itself may regulate many metabolic pathways that are vital to reproduction, growth, and health (4). Particularly, nitric oxide plays an important role in steroidogenesis, oviductal functions, ovulation, embryo implantation, maintenance of pregnancy, and the initiation of labor (5–7). Early embryonic death, before or during the implantation stage, is a major factor determining litter size at birth (8–10).

Despite a crucial role for arginine in placental and fetal development (11), little is known about the effects of exogenous L-arginine on the reproductive performance of female animals. A recent study with gilts demonstrated that dietary supplementation of 1% (wt:wt) L-arginine between d 30 and 114 of gestation increased the number and litter birth weight of live-born piglets by 22 and 24%, respectively (12). Similarly, supplementing 25 g L-arginine to the diet per day for the primiparous or multiparous sows between d 14 and 28 of pregnancy increased the number of live-born piglets by 1 without affecting the average birth weight (13). However, these previous studies focused only on litter size at birth. It is unknown whether arginine treatment during early gestation can enhance embryonic/fetal survival or whether an early effect of arginine supplementation can be carried over to parturition. Additionally, the underlying mechanisms for the beneficial action of arginine on pregnancy outcome remain elusive.

We hypothesized that arginine supplementation during early gestation may improve embryonic survival. The present study was conducted to test this hypothesis in a series of 4 experiments involving pregnant rats.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Rats and diet. All rats used in this study were humanely managed according to the established guidelines of the China Department of Agriculture. The experimental protocol was approved by the China Agricultural University Animal Care and Use Committee. A total of 145 virgin, female Sprague-Dawley rats, aged 2.5–3.0 mo and weighing 234 ± 0.6 g (means ± SEM), were obtained from the Beijing Laboratory Animal Center (Beijing, China). They were individually housed in a temperature- and light-controlled room with the temperature set at 23°C and the lighting schedule set at 12 h light/12 h dark. The rats consumed feed and water ad libitum.

After 3 d of acclimatization, daily vaginal smears were taken to determine the estrous cycle of each rat (14). Rats with abnormal estrus cycles were excluded from use in experiments. Pregnancy was induced by overnight caging of a proestrous female with a male of proven fertility. The next day, the presence of a vaginal plug or spermatozoa in the vaginal smear was termed as d 1 of pregnancy. From this pool of pregnant rats, 120 were chosen randomly for use in the following 4 experiments. The mean initial body weight of these rats in the control or treatment group did not differ.

Expt. 1 was conducted to determine the effect of dietary arginine supplementation during the whole period of pregnancy on litter size and birth weights of rat pups. Twenty-four pregnant rats were assigned randomly to 1 of the 2 treatment groups, representing supplementation with either 1.3% (wt:wt) L-arginine-HCl (Ajinomoto) or 2.2% (wt:wt) L-alanine (isonitrogenous control) (12) to a corn-, soybean meal-, flour-, and fishmeal-based rodent nonpurified diet (catalog no. 2005–0007-Ka112, Science Australia United Efforts Incorporation). There were 12 dams per treatment. Feed processing was conducted by the Science Australia United Efforts. Dietary contents were: digestible energy (13.4 MJ/kg), protein [21.9% (wt:wt)], calcium [1.46% (wt:wt)], total phosphorus [0.92% (wt:wt)], and available phosphorus [0.75% (wt:wt)]. The analyzed contents (%, wt:wt) of amino acids in alanine- and arginine-supplemented diets, as well as the nonsupplemented basal diet, are summarized in Table 1. At birth, litter size and birth weights of rat pups were recorded. In addition, we measured daily feed intake of dams and their body weights during periparturition and postparturition.


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  		TABLE 1 The analyzed contents of amino acids in the alanine- and arginine-supplemented rodent nonpurified diets and in the nonsupplemented basal diet

 
Expt. 2 was conducted to determine the effect of dietary arginine supplementation between d 1 and 7 of gestation on litter size and birth weights of rat pups. Forty pregnant rats were assigned randomly to be fed the isonitrogenous control (alanine-supplemented) or the arginine-supplemented diet between d 1 and 7 of gestation as described in Expt. 1 and then fed the basal diet until parturition. At birth, litter size and birth weights of rat pups were measured. In addition, we measured daily feed intake of dams and their body weights on d 7.

Expt. 3 was conducted to determine the effect of dietary arginine supplementation on the number of implantation sites. Thirty-six pregnant rats were fed 1 of the 2 test diets between d 1 and the morning of d 7, as described in Expt. 2. On d 7, after all rats were anesthetized with sodium pentobarbital and killed, uterine horns were quickly exposed and the number of implantation sites was recorded. In addition, implantation sites of the uterus were immediately obtained and frozen in liquid nitrogen for subsequent analysis. On d 7 of pregnancy, implantation sites were large and could be counted without magnification.

Expt. 4 was conducted to determine the effect of dietary arginine supplementation on concentrations of amino acids, urea, and nitric-oxide metabolites (nitrite and nitrate). Twenty pregnant rats were fed either the isonitrogenous control (alanine supplemented) or the arginine-supplemented diet between mating and the evening of d 4 as described in Expt. 1 and then food was removed from cage feeders. The rats received only water until 1000 on d 5, when all rats were anesthetized with sodium pentobarbital and blood samples were taken from the abdominal aorta. The blood samples were centrifuged at 3500 x g; 10 min (Ciji 800 Model Centrifuge, Surgical Instrument Factory) and serum was stored at –20°C until analysis.

    Chemical analyses. Nitrite and nitrate in serum were determined by reducing nitrate to nitrite and derivatizing nitrite with the Griess reagents (15) using an assay kit from Nanjing Jiancheng Biochemistry. Serum free amino acids were analyzed using a S-433D Amino Acid Analyser (Sykam), as previously described (16). Serum urea was measured using a Biochemical Analytical instrument (Bayer, Manufactured Bayer Diagnostics Manufacturing) according to the method of Krieg et al. (17).

    Western blot analysis. Protein levels for inducible nitric-oxide synthase (iNOS) and endothelial nitric-oxide synthase (eNOS) at uterine implantation sites were determined by western blot analysis. Uterine implantation sites were homogenized in radioimmunoprecipitation assay lysis buffer containing protease inhibitor cocktails (Amresco). After 30 min incubation, homogenates were centrifuged at 14,000 x g; 15 min at 4°C. Then supernatants were collected and stored at –80°C. Protein concentrations were determined by using the BCA protein assay kit (Pierce). Equal amounts of proteins (40, 30, and 20 µg total protein for iNOS, β-actin, and eNOS, respectively) were electrophoresed (Bio-Rad) on SDS-polyacrylamide gels. Proteins were electrotransferred to a polyvinylidene difluoride membrane (Millipore) and blocked with 5% nonfat dry milk at 4°C overnight. The transfer efficiency was controlled by gel staining with Coomassie Blue. Prestained protein markers (Fermentas) were analyzed in each gel. Samples were incubated with rabbit anti-rat polyclonal antibodies (1:1000 dilution for 2 h at room temperature or overnight at 4°C) against eNOS or iNOS (Santa Cruz Biochemistry). After being washed with Tris-Tween-20 buffer (pH 7.4), membranes were incubated with the horseradish peroxidase-conjugated goat anti-rabbit IgG (ZSGB-BIO) for 1 h at room temperature. The membrane was exposed to the X-ray film for 1 min. Band densities were detected with the western blotting luminence reagent (Santa Cruz Biochemistry) and quantified using BandScan software 5.0 (Glyko).

    Statistical analysis. Data were analyzed using the procedures of SAS (SAS Institute) for a randomized complete block design. A pregnant dam was considered as the experimental unit. Data were analyzed using the unpaired t test of SAS (version 8.0, SAS Institute). Results are expressed as means ± SEM. P < 0.05 was considered significant.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
Dietary arginine supplementation throughout pregnancy (Table 2) or between d 1 and 7 of pregnancy (Table 3) did not affect feed intake (expressed per kilogram body weight) or maternal weight gain but increased (P < 0.01) the litter size of rat pups by 30%. Birth weights of rat pups or variation of birth weights did not differ between control and arginine-supplemented dams in either experiment. Regardless of the period of arginine supplementation, total litter birth weight, based on the total number of live-born rats per litter, was higher (P < 0.05) in the arginine-supplemented group compared with the control group. The ratio of male:female rat pups did not differ between the 2 groups (Table 3).


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  		TABLE 2 Reproductive performance of rats fed diets with or without arginine supplementation during pregnancy (Expt. 1 and 2)1

 

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  		TABLE 3 The number of implantation sites (Expt. 3) and serum concentrations of nitric-oxide metabolites and urea (Expt. 4) in rats fed diets with or without arginine supplementation1

 
When pregnant rats were supplemented with arginine between d 1 and 7 of gestation, the number of implantation sites was increased by 29% on d 7, compared with the control group (Table 3) (representative western blots for iNOS, eNOS, and β-actin proteins at the implantation sites of the uterus shown in Figs. 1 and 2, respectively). Ratios of iNOR or eNOS to β-actin were calculated to normalize expression of the NOS protein. Compared with the control group, dietary arginine supplementation increased (P < 0.05) protein levels for iNOS by 35% (0.677 ± 0.04 vs. 0.502 ± 0.02 Fig. 1) and eNOS by 37% (0.269 ± 0.018 vs. 0.197 ± 0.019) at the implantation sites (Fig. 2).


Figure 1
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  		FIGURE 1  Representative western blots for iNOS and β-actin proteins at the implantation sites of the uterus in rats fed the arginine-supplemented diet (Arg) or the alanine-supplemented (isonitrogenous control) diet (Ala). The diets of rats were supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) between d 1 and 7 of gestation. At the end of the supplementation, implantation sites of the uterus were obtained for western blot analysis of iNOS protein.

 

Figure 2
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  		FIGURE 2  Representative western blots for eNOS and β-actin proteins at the implantation sites of the uterus in rats fed the arginine-supplemented diet (Arg) or the alanine-supplemented (isonitrogenous control) diet (Ala). The diets of rats were supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L-alanine (isonitrogenous control) between d 1 and 7 of gestation. At the end of the supplementation, implantation sites of the uterus were obtained for western blot analysis of eNOS protein.

 
Concentrations of nitric-oxide metabolites (nitrite plus nitrate) were 39% greater (P < 0.05), but concentrations of urea were 15% lower, in the serum of arginine-supplemented rats compared with the control group (Table 3). Concentrations of arginine, proline, glutamine, and ornithine in maternal serum were 38% (P < 0.01), 15% (P < 0.05), 29% (P < 0.01), and 33% (P < 0.05) higher, respectively, in response to the arginine treatment (Table 4). Serum concentrations of other amino acids did not differ between the 2 treatment groups (data not shown).


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  		TABLE 4 Serum concentrations of amino acids in rats fed diets with or without arginine supplementation1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Recent studies have shown that dietary arginine supplementation increases litter size in pigs (12,13). However, little is known about a role for arginine in regulating embryo implantation or survival during early pregnancy. Results of the present work demonstrate that supplementing arginine to diets for female rats either throughout the entire pregnancy or between d 1 and 7 of gestation increased litter size (Table 2). Further, we found that the arginine treatment increased the number of surviving embryos on d 7 (Table 3) and such an early effect could be carried on until parturition (Table 2). Also, the effect of arginine supplementation was not likely due to a nonspecific increase in nitrogen intake from the diet. To our knowledge, this is the first study to determine the effect of dietary arginine supplementation on embryonic mortality during early gestation in mammals. Our findings also extend and confirm the previous reports of a beneficial role for arginine in increasing the number of live-born piglets at birth (12,13). Because 30–70% of embryonic losses occur before or during implantation (18–21), these exciting results have important implications for pregnancy outcome in mammals.

Through modulation of the intrauterine environment and endocrine status, maternal nutrition is a major factor affecting the survival, growth, and development of embryos and fetuses (22). Among dietary components, amino acids have recently received much attention, because they are the building blocks of proteins and regulators of key metabolic pathways (4,23). Accordingly, oviductal and uterine fluids contain large amounts of free amino acids, suggesting their role in preimplantation development (24). In addition, fetal fluids are rich in the arginine family of amino acids, including arginine, citrulline, ornithine, and glutamine, during early pregnancy when placental growth is most rapid (25–27).

Preimplantation embryos express several amino acid transporters that selectively transport intrauterine arginine into embryos (28). Arginine is required not only for protein accretion, but also for the generation of various molecules with enormous physiological importance (3). These arginine-derived substances include nitric oxide and polyamines that regulate DNA and protein synthesis, as well as cell proliferation (2). Results of the current study indicate that dietary arginine supplementation increased systemic production of nitric oxide (Table 4). Additionally, expression of both iNOS and eNOS proteins was enhanced for augmented synthesis of nitric oxide at the implantation sites of the uterus in arginine-supplemented rats (Figs. 1 and 2). Available evidence shows that nitric oxide is required for increased vascular permeability, normal embryonic development, and uterine quiescence at the sites of blastocyst apposition (29,30). In support of this, embryonic mortality is increased and intrauterine growth is compromised in mice with the knockout of endothelial NOS (5). Furthermore, an inhibition of NOS during pregnancy reduced embryonic/fetal survival and growth in rats (31–33). Therefore, dietary arginine supplementation improves the survival and development of embryos and fetuses possibly via enhancing the availability of nitric oxide.

The small intestine of adult mammals (including rats) extensively catabolizes dietary arginine (34). However, we found that serum concentrations of arginine, proline, ornithine, and glutamine were higher in the arginine-supplemented group than in the control group (Table 4). Thus, a significant quantity of supplemental arginine enters the portal vein and systemic circulation for utilization by extraintestinal tissues. Products of arginine catabolism via the arginase pathway include ornithine, proline, and glutamine (3). Ornithine and proline can be used for the synthesis of polyamines in the uterus and placenta (35,36), which are essential for cell proliferation and differentiation. In addition, glutamine is a fuel for the developing embryos (37), as well as a regulator of synthesis of nitric oxide (38) and polyamines (39). Through mammalian target of rapamycin signaling, glutamine also regulates intracellular protein turnover, therefore affecting the survival and growth of embryos and fetuses (11). Moreover, glutamine metabolism via phosphate-dependent glutaminase yields glutamate, an amino acid for the synthesis of glutathione, which is the major antioxidant in cells (40).

Arginine is an allosteric activator of N-acetylglutamate synthase, which synthesizes N-acetylglutamate (an activator of carbamylphosphate synthase-I) from glutamate and acetyl-CoA (3). Thus, arginine is required to maintain the urea cycle in both the liver and small intestine in an active state. Consistent with the reports from studies with pigs (12), serum urea concentrations were lower in arginine-supplemented rats than in the control group (Table 4). This result suggests that ammonia production is reduced or ammonia removal is enhanced in response to arginine supplementation. Because embryonic development is compromised by high levels of ammonia (41), a low concentration of extracellular ammonia may contribute to the beneficial effect of arginine supplementation on pregnancy outcome in mammals.

In conclusion, supplementing arginine to the diet for female rats during early gestation or throughout pregnancy increases implantation sites, embryonic survival, and litter size in association with elevated levels of arginine and its metabolites (nitric oxide, ornithine, and proline) but reduced concentrations of urea in serum. Our novel findings have important implications for reducing embryonic mortality and improving pregnancy outcome in mammals.


   ACKNOWLEDGMENTS
 
We thank Dr. Phil Thacker, Dr. Guoshi Liu, Professor Shenming Zeng, Professor Shien Zhu, Professor Jianhui Tian, and Dr. Yachun Wang for helpful discussion and technical assistance.


   FOOTNOTES
 
1 Supported by the National Science and Technology Pillar Program in the Eleventh Five-Year Plan Period (no. 2006 BAD12B07-3, 2006 BAD14B01, and 2006 BAD14B03-2), National Natural Science Foundation of China (no. u0731001), Beijing Municipal Natural Science Foundation (no. 6082017), and Texas AgriLife Research (no. H-8200). Back

2 Author disclosures: X. F. Zeng, F. L. Wang, X. Fan, W. J. Yang, B. Zhou, P. F. Li, Y. L. Yin, G. Y. Wu, and J. J. Wang, no conflicts of interest. Back

Manuscript received 26 March 2008. Initial review completed 13 April 2008. Revision accepted 14 May 2008.


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 Introduction
 Materials and Methods
 Results
 Discussion
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