[Show abstract][Hide abstract] ABSTRACT: The frequency of multiple fetuses has increased in human pregnancies due to assisted reproductive technologies. This translates into a greater proportion of premature and low-birth weight infants in the United States and worldwide. In addition, improvements in sheep breeding have resulted in new breeds with increased litter size but reduced fetal survival and birth weight. Currently, there are no treatments for preventing fetal growth restriction in humans or sheep (an established model for studying human fetal physiology) carrying multiple fetuses. In this work, Booroola Rambouillet ewes (FecB+/-) with 2-4 fetuses were fed a diet providing 100% of NRC-recommended nutrient requirements. Between d 100 and 121 of gestation, ewes received an i.v. bolus injection of either saline solution or 345 μmol arginine-HCl/kg body weight 3 times daily. The arginine treatment reduced (P < 0.05) the percentage of lambs born dead by 23% while increasing (P = 0.05) the percentage of lambs born alive by 59%. The i.v. administration of arginine enhanced (P < 0.05) the birth weights of quadruplets by 23% without affecting maternal body weight. The improved pregnancy outcome was associated with an increase in maternal plasma concentrations of arginine, ornithine, cysteine, and proline, as well as a decrease in circulating levels of ammonia and β-hydroxybutyrate. These novel results indicate that parenteral administration of arginine to prolific ewes ameliorated fetal mortality and growth retardation. Our findings provide support for experiments to assess the clinical use of arginine to enhance fetal growth and survival in women gestating multiple fetuses.
Journal of Nutrition 03/2011; 141(5):849-55. DOI:10.3945/jn.111.138172 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intrauterine growth restriction (IUGR) is a major health problem worldwide that currently lacks an effective therapeutic solution. This study was conducted with an ovine IUGR model to test the hypothesis that parenteral administration of l-arginine (Arg) is effective in enhancing fetal growth. Beginning on d 28 of gestation, ewes were fed a diet providing 100% (control-fed) or 50% (underfed) of NRC-recommended nutrient requirements. Between d 60 of gestation and parturition, underfed ewes received i.v. infusions of saline or 155 micromol Arg-HCl/kg body weight 3 times daily, whereas control-fed ewes received only saline. The birth weights of lambs from saline-infused underfed ewes were 23% lower (P < 0.01) than those of lambs from control-fed dams. Administration of Arg to underfed ewes increased (P < 0.01) concentrations of Arg (69%), ornithine (55%), proline (29%), methionine (37%), leucine (36%), isoleucine (35%), cysteine (19%), and FFA (43%) in maternal serum, decreased maternal circulating levels of ammonia (18%) and triglycerides (32%), and enhanced birth weights of lambs by 21% compared with saline-infused underfed ewes. There was no difference in birth weights of lambs between the control-fed and the Arg-infused underfed ewes. These novel results indicate that parenteral administration of Arg to underfed ewes prevented fetal growth restriction and provide support for its clinical use to ameliorate IUGR in humans. The findings also lay a new framework for studying cellular and molecular mechanisms responsible for the beneficial effects of Arg in regulating conceptus growth and development.
Journal of Nutrition 07/2010; 140(7):1242-8. DOI:10.3945/jn.110.125658 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cholesterol and docosahexaenoic acid (DHA) are important nutrients for neural development of infants. However, little is known
about the effect of cholesterol or DHA on concentrations of amino acids (AA) in neonatal tissues. This study was conducted
with the piglet (an established model for studying human infant nutrition) to test the hypothesis that dietary supplementation
with the lipids may modulate AA availability in tissues. Sixteen newborn pigs were nursed by sows for 24h and then assigned
to one of four treatment groups, representing supplementation with 0.0% (control), 0.2% cholesterol, 0.2% DHA, or cholesterol
plus DHA to the basal milk-formula. All piglets were euthanized at 49days of age. In brain, cholesterol supplementation reduced
(P<0.05) concentrations of glutamate, serine, glutamine, threonine, β-alanine, alanine, methionine, isoleucine, leucine, and
γ-aminobutyrate but increased (P<0.05) concentrations of glycine and lysine, whereas DHA supplementation similarly affected (P<0.05) concentrations of the same AA (except for isoleucine and lysine) and taurine. In addition, concentrations of most
AA in liver, muscle and plasma were substantially altered by dietary supplementation of cholesterol and DHA in a tissue-dependent
manner. Further, DHA reduced concentrations of carnosine in skeletal muscle, as well as ammonia in both plasma and brain.
The results reveal that cholesterol and DHA can regulate AA metabolism and availability in various tissues of piglets. These
novel findings have important implications for designing the next generation of infant formula to optimize neonatal growth
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO), synthesized from l-arginine by tetrahydrobiopterin (BH4)-dependent NO synthase (NOS), is critical for neurological and muscular development and function. This study was designed to test the hypothesis that cholesterol and docosahexaenoic acid (DHA) may modulate the arginine-NO pathway in tissues of the young pig. Sixteen newborn pigs were nursed by sows for 24h and then assigned to one of four treatment groups, representing supplementation with 0.0%, 0.2% cholesterol, 0.2% DHA, or cholesterol plus DHA to the basal milk-formula. All piglets were euthanized at 49 days of age. Brain, liver and gastrocnemius muscle were analyzed for BH4, NADPH and arginine, GTP cyclohydrolase-I (GTP-CH) and NOS activities, and NOS protein isoforms. Hepatic NOS activity was below the detection limit in all pigs. DHA supplementation (P<0.01) increased GTP-CH activities, as well as BH4 and NADPH concentrations in brain, liver, and muscle by 24-46%, while enhancing (P<0.05) NOS activities by 45-48% in brain and muscle. Dietary cholesterol supplementation increased (P<0.05) NOS and GTP-CH activities by 17-26% in brain but had no effect in liver or muscle. The enhanced NOS activity in the brain or muscle of cholesterol- or DHA-supplemented piglets was attributable to the combined effects of increased eNOS and nNOS activation (changes in phosphorylation levels) and total iNOS protein. Additionally, DHA and cholesterol enhanced (P<0.05) arginine concentrations in brain (35-42%), but not in liver or muscle. These tissue-specific effects of cholesterol and DHA on NO synthesis may play an important role in postnatal growth and development.
[Show abstract][Hide abstract] 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.