Maternal nutrition during gestation, especially dietary protein intake, is a key determinant in embryonic survival, growth, and development. Low maternal dietary protein intake can cause embryonic losses, intra-uterine growth restriction, and reduced postnatal growth due to a deficiency in specific amino acids that are important for cell metabolism and function. Of note, high maternal dietary protein intake can also result in intra-uterine growth restriction and embryonic death, due to amino acid excesses, as well as the toxicity of ammonia, homocysteine, and H2S that are generated from amino acid catabolism. Maternal protein nutrition has a pronounced impact on fetal programming and alters the expression of genes in the fetal genome. As a precursor to the synthesis of molecules (e.g. nitric oxide, polyamines, and creatine) with cell signaling and metabolic functions, L-arginine (Arg) is essential during pregnancy for growth and development of the conceptus. With inadequate maternal dietary protein intake, Arg and other important amino acids are deficient in mother and fetus. Dietary supplementation of Arg during gestation has been effective in improving embryonic survival and development of the conceptus in many species, including humans, pigs, sheep, mice, and rats. Both the balance among amino acids and their quantity are critical for healthy pregnancies and offspring. Impact statement This review aims at: highlighting adverse effects of elevated levels of ammonia in mother or fetus on embryonic/fetal survival, growth, and development; helping nutritionists and practitioners to understand the mechanisms whereby elevated levels of ammonia in mother or fetus results in embryonic/fetal death, growth restriction, and developmental abnormalities; and bringing, into the attention of nutritionists and practitioners, the problems of excess or inadequate dietary intake of protein or amino acids on pregnancy outcomes in animals and humans. The article provides new, effective means to improve embryonic/fetal survival and growth in mammals.

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Impacts of maternal dietary protein intake on fetal survival, growth, and development:

In pigs, as in other species, fetal growth retardation is associated with reduced birth weight and increased risk of fetal and neonatal death. As there are few opportunities after birth to remedy the detrimental effects of low birth weight, it is important to understand both the intrinsic and extrinsic factors associated with inadequate fetal growth and to determine when growth retarded fetuses deviate from the growth trajectory of their normal sized littermates. Inadequately grown pig fetuses can be identified statistically as early as day 30 of the 114 days of gestation, indicating that limited uterine space is not a primary determinant of fetal growth. Comparisons of the smallest fetus within a litter with a normal sized sibling reveal that inadequately grown fetuses have altered endocrine status and lower circulating concentrations of many essential amino acids. In addition, the placenta supplying the smallest fetus is disproportionately small and has a reduced capacity to transport amino acids. Understanding the timing and the causes of fetal growth retardation in pigs may help us to devise appropriate strategies to reduce the incidence and hence the detrimental postnatal consequences of runting.

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Causes and conseq uences of fetal growth retardation in pigs

https://www.cell.com/cell-metabolism/pdf/S1550-4131(20)30186-8.pdf

A Nutrient-Sensing Transition at Birth Triggers Glucose-Responsive Insulin Secretion

l-Glutamate (Glu) has traditionally not been considered as a nutrient needed in diets for humans and other animals (including swine) due to the unsubstantiated assumption that animals can synthesize sufficient amounts of Glu to meet their needs. The lack of knowledge about Glu nutrition has contributed to suboptimal efficiency of global livestock production. Over the past 25 years, there has been growing interest in Glu metabolism in the pig, which is an agriculturally important species and also a useful model for studying human biology. Because of analytical advances in its analysis, Glu is now known to be a highly abundant free amino acid in milk and intracellular fluid, a major constituent of food and tissue proteins, and a key regulator of gene expression, cell signaling, and anti-oxidative reactions. Emerging evidence shows that dietary supplementation with 2% Glu maintains gut health and prevents intestinal dysfunction in weanling piglets, while enhancing their growth performance and survival. In addition, the inclusion of 2% Glu is required for dietary arginine to maximize the growth performance and feed efficiency in growing pigs, whereas dietary supplementation with 2% Glu reduces the loss of skeletal muscle mass in endotoxin-challenged pigs. Furthermore, supplementing 2% Glu to a corn- and soybean-meal-based diet promotes milk production by lactating sows. Thus, an adequate amount of dietary Glu as a quantitatively major nutrient is necessary to support maximum growth, development, and production performance of swine. These results also have important implications for improving the nutrition and health of humans and other animals.

L-Glutamate nutrition and metabolism in swine.

As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (MTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID-19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.

Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans.

The mammalian placenta is essential for supplying nutrients (e.g., amino acids and water) and oxygen from the mother to fetus and for removing fetal metabolites (e.g., ammonia and CO2 ) from fetus to mother. Thus, placental growth and development are determinants of fetal survival, growth, and development. Indeed, low birth weight is closely associated with reduced placental growth. Providing gestating gilts or sows with dietary supplementation of arginine and glutamine, increases placental growth (including vascular growth), improves embryonic/fetal growth and survival, and reduces the large variation in birth weight among litters. These two amino acids serve as building blocks for tissue protein as well as substrates for the production of polyamines and nitric oxide, which stimulate DNA and protein synthesis and angiogenesis and vascular growth in the placenta. These recent findings not only greatly advance the field of mammalian amino acid metabolism and nutrition, but also provide practical, mechanism-based methods to enhance reproductive efficiency in swine. These results may also help improve embryonic/fetal survival and growth in other livestock species (e.g., sheep and cattle) and in humans.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mrd.22809

Functional amino acids in the development of the pig placenta.

Proteins are large polymers of amino acids (AAs) linked via peptide bonds, and major components for the growth and development of tissues in zoo animals (including mammals, birds, and fish). The proteinogenic AAs are alanine, arginine, aspartate, asparagine, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. Except for glycine, they are all present in the L-isoform. Some carnivores may also need taurine (a nonproteinogenic AA) in their diet. Adequate dietary intakes of AAs are necessary for the growth, development, reproduction, health and longevity of zoo animals. Extensive research has established dietary nutrient requirements for humans, domestic livestock and companion animals. However, this is not true for many exotic or endangered species found in zoos due to the obstacles that accompany working with these species. Information on diets and nutrient profiles of free-ranging animals is needed. Even with adequate dietary intake of crude protein, dietary AAs may still be unbalanced, which can lead to nutrition-related diseases and disorders commonly observed in captive zoo species, such as dilated cardiomyopathy, urolithiasis, gut dysbiosis, and hormonal imbalances. There are differences in AA metabolism among carnivores, herbivores and omnivores. It is imperative to consider these idiosyncrasies when formulating diets based on established nutritional requirements of domestic species. With optimal health, populations of zoo animals will have a vastly greater chance of thriving in captivity. For endangered species especially, maintaining stable captive populations is crucial for conservation. Thus, adequate provision of AAs in diets plays a crucial role in the management, sustainability and expansion of healthy zoo animals.

Amino Acid Nutrition for Optimum Growth, Development, Reproduction, and Health of Zoo Animals

Dietary supplementation with 0.4 or 0.8% l-arginine (Arg) to gilts between days 14 and 25 of gestation enhances embryonic survival and vascular development in placentae; however, the underlying mechanisms are largely unknown. This study tested the hypothesis that Arg supplementation stimulated placental expression of mRNAs and proteins that enhance angiogenesis, including endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), placental growth factor (PGF), GTP cyclohydrolase-I (GTP-CH1), ornithine decarboxylase (ODC1), and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2). Beginning on the day of breeding, gilts were fed daily 2 kg of a corn–soybean meal-based diet supplemented with 0.0 (control), 0.4, or 0.8% Arg. On day 25 of gestation, gilts were hysterectomized to obtain uteri and conceptuses for histochemical and biochemical analyses. eNOS and VEGFR1 proteins were localized to endothelial cells of maternal uterine blood vessels and to the uterine luminal epithelium, respectively. Compared with the control, dietary supplementation with 0.4 or 0.8% Arg increased (P < 0.05) the amounts of nitrite plus nitrate (NOx; oxidation products of NO) and polyamines in allantoic and amniotic fluids, concentrations of NOx, tetrahydrobiopterin (BH4, an essential cofactor for all NOS isoforms) and polyamines in placentae, as well as placental protein abundances of GTP-CH1 (the key enzyme for BH4 production) and ODC1 (the key enzyme for polyamine synthesis). Placental  mRNA levels for GTP-CH1, eNOS, PGF, VEGF, and VEGFR2 increased in response to both 0.4% and 0.8% Arg supplementation. Collectively, these results indicate that dietary Arg supplementation to gilts between days 14 and 25 of pregnancy promotes placental angiogenesis by increasing the expression of mRNAs and proteins for angiogenic factors as well as NO and polyamine syntheses.

Dietary supplementation with L-arginine between days 14 and 25 of gestation enhances NO and polyamine syntheses and the expression of angiogenic proteins in porcine placentae.

Abstract Background Most embryonic loss in pigs occurs before d 30 of gestation. Dietary supplementation with L -arginine (Arg) during early gestation can enhance the survival and development of conceptuses (embryo/fetus and its extra-embryonic membranes) in gilts. However, the underlying mechanisms remain largely unknown. Methods Between d 14 and 30 of gestation, each gilt was fed daily 2 kg of a corn- and soybean-meal based diet (12% crude protein) supplemented with either 0.4% Arg (as Arg-HCl) or an isonitrogenous amount of L -alanine (Control). There were 10 gilts per treatment group. On d 30 of gestation, gilts were fed either Arg-HCl or L -alanine 30 min before they were hysterectomized, followed by the collection of placentae, embryos, fetal membranes, and fetal fluids. Amniotic and allantoic fluids were analyzed for nitrite and nitrate [NOx; stable oxidation products of nitric oxide (NO)], polyamines, and amino acids. Placentae were analyzed for syntheses of NO and polyamines, water and amino acid transport, concentrations of amino acid-related metabolites, and the expression of angiogenic factors and aquaporins (AQPs). Results Compared to the control group, Arg supplementation increased ( P &lt; 0.05) the number of viable fetuses by 1.9 per litter, the number and diameter of placental blood vessels (+ 25.9% and + 17.0% respectively), embryonic survival (+ 18.5%), total placental weight (+ 36.5%), the total weight of viable fetuses (+ 33.5%), fetal crown-to-rump length (+ 4.7%), and total allantoic and amniotic fluid volumes (+ 44.6% and + 75.5% respectively). Compared to control gilts, Arg supplementation increased ( P &lt; 0.05) placental activities of GTP cyclohydrolase-1 (+ 33.1%) and ornithine decarboxylase (+ 29.3%); placental syntheses of NO (+ 26.2%) and polyamines (+ 28.9%); placental concentrations of NOx (+ 22.5%), tetrahydrobiopterin (+ 21.1%), polyamines (+ 20.4%), cAMP (+ 27.7%), and cGMP (+ 24.7%); total amounts of NOx (+ 61.7% to + 96.8%), polyamines (+ 60.7% to + 88.7%), amino acids (+ 39% to + 118%), glucose (+ 60.5% to + 62.6%), and fructose (+ 41.4% to + 57.0%) in fetal fluids; and the placental transport of water (+ 33.9%), Arg (+ 78.4%), glutamine (+ 89.9%), and glycine (+ 89.6%). Furthermore, Arg supplementation increased ( P &lt; 0.05) placental mRNA levels for angiogenic factors [ VEGFA120 (+ 117%), VEGFR1 (+ 445%), VEGFR2 (+ 373%), PGF (+ 197%), and GCH1 (+ 126%)] and AQPs [ AQP1 (+ 280%), AQP3 (+ 137%), AQP5 (+ 172%), AQP8 (+ 165%), and AQP9 (+ 127%)]. Conclusion Supplementing 0.4% Arg to a conventional diet for gilts between d 14 and d 30 of gestation enhanced placental NO and polyamine syntheses, angiogenesis, and water and amino acid transport to improve conceptus development and survival. 

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Dietary supplementation with 0.4% L-arginine between days 14 and 30 of gestation enhances NO and polyamine syntheses and water transport in porcine placentae

Cassandra M Herring

Papers

Impacts of maternal dietary protein intake on fetal survival, growth, and development:

Functional amino acids in the development of the pig placenta.

Amino Acid Nutrition for Optimum Growth, Development, Reproduction, and Health of Zoo Animals

Dietary supplementation with L-arginine between days 14 and 25 of gestation enhances NO and polyamine syntheses and the expression of angiogenic proteins in porcine placentae.

Dietary supplementation with 0.4% L-arginine between days 14 and 30 of gestation enhances NO and polyamine syntheses and water transport in porcine placentae