The value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) parameters in analysis with fetal malnutrition neonates.

Objective To assess the association between fetal malnutrition (FM) and the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) in singleton term appropriate for gestational age (AGA) neonates. Methods This cross-sectional observational study was performed with 4340 singleton, term AGA neonates without perinatal disease over a two-year period. Results A total of 4320 neonates were evaluated in this study. Those diagnosed with fetal malnutrition, 284 (6%) neonates, were compared with 150 healthy term AGA neonates. Gestational week, birth weight, birth height, head circumference, maternal age, last pregnancy weight, and status of income of the FM group were found to be lower when compared to the control group (P = 0.011). Low last pregnancy weight (P = 0.017) and low level of income (P = 0.042) were found to be factors that affect the presence of FM. The NLR and PLR were found to be significantly higher in the FM group compared with term AGA healthy controls. In correlation analyses, there was a negative correlation between the NLR and PLR with fetal nutritional status (P = 0.011 and P < 0.001, respectively). When the NLR level was taken as 4.51, the sensitivity and specificity of the test for FM were calculated as 81.2% and 80.8%, respectively [area under the receiver-operating characteristic curve (AUROC): 0.81]; when the PLR level was taken as 155.4, the sensitivity and specificity of the test for FM were calculated as 87.0% and 85.4%, respectively (AUROC: 0.94). Conclusion Cord-blood NLR and PLR negatively correlate with term FM AGA neonates.

Central Hematocrit Levels in Fetal Malnourished Term Infants.

BACKROUND: Fetal malnutrition is especially important for common chronic diseases in adult life. They could potentially be prevented by achieving optimal fetal nutrition. OBJECTIVE: The aim of this study was to investigate hematocrit levels of malnourished, term, appropriate for gestational age (AGA) neonates. SUBJECTS AND METHODS: A total of 80 AGA neonates (between 10% and 90% percentiles interval according to birth week), born with spontaneous vaginal delivery between 37 and 42 weeks of gestation, detected by both last menstrual period and ultrasonography measurements, were included in the study. Neonates with fetal malnutrition constituted the study group and the control group consisted of well-nourished neonates. We analyzed central venous hematocrit levels obtained 4 hours after birth and maternal risk factors for both groups. RESULTS: Although there were no differences in gestational age, head circumference, maternal factors (gravidity, parity, abortions and curettage counts, maternal tobacco use, preeclampsia, hypertension, diabetes mellitus, gestational diabetes mellitus, and history of urinary tract infections), first minute APGAR scores, and sex, Clinical Assessment of Nutritional Status score was lower (29.91±2.87 vs. 21.25±1.65) and hematocrit levels were higher (51.33±2.740 vs. 59.53±5.094) in the fetal malnutrition group (P<0.0001). CONCLUSIONS: Central hematocrit levels in malnourished term AGA neonates were found significantly higher than well-nourished term AGA newborns.

Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status.

Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.

Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex.

Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.

Implications of intrauterine protein malnutrition on prostate growth, maturation and aging.

AIMS: Maternal malnutrition by low protein diet is associated with an increased incidence of metabolic disorders and decreased male fertility in adult life. This study aimed to assess the impact of maternal protein malnutrition (MPM) on prostate growth, tissue organization and lesion incidence with aging. MAIN METHODS: Wistar rat dams were distributed into two groups, which were control (NP; fed a normal diet containing 17% protein) or a restricted protein diet (RP, fed a diet containing 6% protein) during gestation. After delivery all mothers and offspring received a normal diet. Biometrical parameters, hormonal levels and prostates were harvested at post-natal days (PND) 30, 120 and 360. KEY FINDINGS: MPM promoted low birth weight, decreased ano-genital distance (AGD) and reduced androgen plasma levels of male pups. Prostatic lobes from RP groups presented reduced glandular weight, epithelial cell height and alveolar diameter. The epithelial cell proliferation and collagen deposition were increased in RP group. Incidences of epithelial dysplasia and prostatitis were higher in the RP offspring than in the NP offspring at PND360. SIGNIFICANCE: Our findings show that MPM delays prostate development, growth and maturation until adulthood, probably as a result of low testosterone stimuli. The higher incidence of cellular dysplasia and prostatitis suggests that MPM increases prostate susceptibility to diseases with aging.

Environmental and genetical aspects of the link between pregnancy, birth size, and type 2 diabetes.

Exposure of the fetus to the intrauterine milieu can have profound effects on the health of the offspring in adulthood. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. Results of a series of studies demonstrate the powerful influence of the mother's metabolic state on whether the emerging adult develops obesity and hyperinsulinemia. Importantly, these attributes can be passed on to the next generation non-genetically and can be reversed and prevented. Such hypothesis has been expanded on by the "Developmental Origins of Health and Disease" (DOHaD) hypothesis which describes the origin of adult disease in terms of fetal developmental 'plasticity' or the ability of the fetus to respond to poor in-utero conditions. A wealth of epidemiological evidence has provided a convincing link between a sub-optimal gestational environment and an increased propensity to develop adult onset metabolic disease. In this paper the factors that participate in the programming of the fetus and infants that lead to endocrine dysfunction in postnatal life are reviewed.

1H-NMR-based metabolic profiling of maternal and umbilical cord blood indicates altered materno-foetal nutrient exchange in preterm infants.

BACKGROUND: Adequate foetal growth is primarily determined by nutrient availability, which is dependent on placental nutrient transport and foetal metabolism. We have used (1)H nuclear magnetic resonance (NMR) spectroscopy to probe the metabolic adaptations associated with premature birth. METHODOLOGY: The metabolic profile in (1)H NMR spectra of plasma taken immediately after birth from umbilical vein, umbilical artery and maternal blood were recorded for mothers delivering very-low-birth-weight (VLBW) or normo-ponderal full-term (FT) neonates. PRINCIPAL FINDINGS: Clear distinctions between maternal and cord plasma of all samples were observed by principal component analysis (PCA). Levels of amino acids, glucose, and albumin-lysyl in cord plasma exceeded those in maternal plasma, whereas lipoproteins (notably low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) and lipid levels were lower in cord plasma from both VLBW and FT neonates. The metabolic signature of mothers delivering VLBW infants included decreased levels of acetate and increased levels of lipids, pyruvate, glutamine, valine and threonine. Decreased levels of lipoproteins glucose, pyruvate and albumin-lysyl and increased levels of glutamine were characteristic of cord blood (both arterial and venous) from VLBW infants, along with a decrease in levels of several amino acids in arterial cord blood. CONCLUSION: These results show that, because of its characteristics and simple non-invasive mode of collection, cord plasma is particularly suited for metabolomic analysis even in VLBW infants and provides new insights into the materno-foetal nutrient exchange in preterm infants.

Adrenal glands are essential for activation of glucogenesis during undernutrition in fetal sheep near term.

In adults, the adrenal glands are essential for the metabolic response to stress, but little is known about their role in fetal metabolism. This study examined the effects of adrenalectomizing fetal sheep on glucose and oxygen metabolism in utero in fed conditions and after maternal fasting for 48 h near term. Fetal adrenalectomy (AX) had little effect on the rates of glucose and oxygen metabolism by the fetus or uteroplacental tissues in fed conditions. Endogenous glucose production was negligible in both AX and intact, sham-operated fetuses in fed conditions. Maternal fasting reduced fetal glucose levels and umbilical glucose uptake in both groups of fetuses to a similar extent but activated glucose production only in the intact fetuses. The lack of fasting-induced glucogenesis in AX fetuses was accompanied by falls in fetal glucose utilization and oxygen consumption not seen in intact controls. The circulating concentrations of cortisol and total catecholamines, and the hepatic glycogen content and activities of key gluconeogenic enzymes, were also less in AX than intact fetuses in fasted animals. Insulin concentrations were also lower in AX than intact fetuses in both nutritional states. Maternal glucose utilization and its distribution between the fetal, uteroplacental, and nonuterine maternal tissues were unaffected by fetal AX in both nutritional states. Ovine fetal adrenal glands, therefore, have little effect on basal rates of fetal glucose and oxygen metabolism but are essential for activating fetal glucogenesis in response to maternal fasting. They may also be involved in regulating insulin sensitivity in utero.

Thioredoxin binding protein-2 inhibits excessive fetal hypoglycemia during maternal starvation by suppressing insulin secretion in mice.

Glucose is a major fuel for fetal development. Fetal blood glucose level is mainly dependent on maternal blood glucose concentration, though it is also regulated by fetal insulin level. Thioredoxin binding protein-2 (TBP-2), which is identical to vitamin D3 up-regulated protein (VDUP1) and thioredoxin interacting protein (Txnip), was recently reported to be a key transcriptional factor controlling glucose metabolism. Here, we elucidated the functions of TBP-2 in maintaining blood glucose homeostasis during the fetal period. TBP-2(+/-) female mice were mated with TBP-2(+/-) male mice; beginning 16.5-d post coitum, pregnant mice were fed or fasted for 24 h. Under conditions of maternal starvation, the blood glucose levels of TBP-2(-/-) fetuses were significantly lower than those of TBP-2(+/+) fetuses, corresponding to the elevated plasma insulin levels of TBP-2(-/-) fetuses compared with those of TBP-2(+/+) fetuses. There was no difference between TBP-2(+/+) and TBP-2(-/-) fetuses in terms of their pancreatic beta-cell masses or the expression of placental glucose transporters under conditions of either maternal feeding or fasting. Thus, during maternal fasting, fetal TBP-2 suppresses excessive insulin secretion to maintain the fetus's glucose levels, implying that TBP-2 is a critical molecule in mediating fetal glucose homeostasis depending on nutrient availability.

Early undernutrition attenuates the inflammatory response in adult rat offspring.

OBJECTIVE: We determined the impact of maternal food restriction during gestation and lactation or lactation alone on basal inflammation and lipopolysaccharide (LPS)-stimulated cytokine induction in adult female offspring. STUDY DESIGN: From 10 days of gestation to term, pregnant rats received either ad libitum (control) feed or were 50% food restricted (FR). Pups were either nursed by their own dams or were cross-fostered to give three groups, namely, Control (AdLib/AdLib), FR during lactation (AdLib/FR) and FR during pregnancy and lactation (FR/FR). All offspring were weaned to ad libitum rat chow. At 9 months of age, basal inflammation and LPS-stimulated cytokine responsiveness were determined in female offspring. RESULTS: The basal CRP levels were elevated in AdLib/FR and FR/FR as compared to Controls. In contrast, LPS induction of IL-1beta and IL-6 was significantly attenuated in the AdLib/FR and FR/FR offspring as compared to the Control group. CONCLUSIONS: These findings suggest that early undernutrition, particularly during prenatal and postnatal periods, affects offspring immune competence by increasing basal inflammation while reducing cytokine induction to inflammatory stimuli.

The late gestation fetal cardiovascular response to hypoglycaemia is modified by prior peri-implantation undernutrition in sheep.

Undernourished late gestation fetuses display asymmetric growth restriction, suggestive of a redistribution of nutritional resources. The modification of fetal organ blood supply in response to acute hypoxia is well characterized, but it is not known whether similar responses occur in response to acute reductions in nutrition, or if such late gestation responses can be influenced by early gestation nutrition. In pregnant sheep, total nutrient requirements were restricted during the peri-implantation period (PI40, 40%; PI50, 50% of total, days 1-31) or in late gestation (L, 50% total, days 104-postmortem). Control animals were fed 100% nutrient requirements. Fetal organ blood flows were measured at baseline, and during acute fetal hypoglycaemia induced by maternal insulin infusion at 125 dGA. Baseline heart rate was increased in PI40 fetuses. During hypoglycaemia, an initial rise in fetal heart rate was followed by a slower fall. Fetal femoral artery blood flow decreased, and adrenal blood flow and femoral vascular resistance increased in all fetuses during hypoglycaemia. These changes were accompanied by increased fetal plasma adrenaline and cortisol, and reduced plasma insulin levels. The maximum femoral artery blood flow response to hypoglycaemia occurred earlier in PI50 and PI40 compared with control fetuses. The late gestation fetal cardiovascular response to acute hypoglycaemia was consistent with a redistribution of combined ventricular output away from the periphery and towards central organs. One element of the peripheral vascular response was modified by peri-implantation nutrient restriction, indicating that nutritional challenges early in gestation can have an enduring impact on cardiovascular control.

The effects of intrauterine undernutrition on pancreas ghrelin and insulin expression in neonate rats.

Ghrelin has a correlation with insulin secretion, beta-cell development, and diabetes in crucial development period. The aim of this study was to compare the changes in plasma ghrelin, insulin, and glucose concentrations, and variation of ghrelin expression in the pancreas in response to intrauterine malnutrition in newborn rats. Pregnant rats at day 2 were randomly divided into two groups: nourished (fed ad libitum; NR) and undernourished rats (UR). The offspring of NR were defined as normal-birth-weight group (NBW, n = 79) and those of UR were defined as low-birth-weight group (LBW, n = 74). Plasma glucose, ghrelin, and serum insulin of both dams and their pups were analyzed at the first day after birth. The entire pancreas was collected for determination of ghrelin and insulin mRNAs, and quantification of pancreas ghrelin and insulin. Immunohistochemical double staining and confocal microscopy were performed on rat pancreas. Birth weight was 5.81 +/- 0.64 and 4.76 +/- 0.23 g in NBW group and LBW group respectively. Fasting plasma ghrelin concentrations in UR group (1382 (1287-1513) pg/ml) were higher than that of NR group (1072 (974-1205) pg/ml). Plasma ghrelin concentrations in the LBW group (2176 (2031-2384) pg/ml) were significantly lower than that of the NBW group (2493 (2311-2675) pg/ml). Undernutrition caused a decrease in plasma insulin concentrations in both UR dams and LBW pups (P < 0.001). Ghrelin mRNA and total ghrelin of pancreas were significantly affected by intrauterine nutrition state. Pancreas insulin concentrations were significantly affected by intrauterine nutrition (P = 0.007). The majority of ghrelin-producing cells were present at the periphery of islets in the NBW group. Ghrelin was colocalized with insulin in ss-cells in LBW group. The percentage of ghrelin-positive cells in the islets of LBW group was significantly higher than that of the NBW group (P < 0.01). Intrauterine undernutrition may affect the birth weight, plasma insulin and ghrelin levels, islet ghrelin expression, and ghrelin cell distribution. It will be interesting to investigate intrauterine nutrition which is involved in islet ghrelin expression and ghrelin cell distribution.

Brief hyperglycaemia in the early pregnant rat increases fetal weight at term by stimulating placental growth and affecting placental nutrient transport.

In pregnant women with type 1 diabetes, suboptimal glucose control in the first trimester is a strong predictor for giving birth to a large fetus. However, the mechanisms underlying this association are unknown. We hypothesized that transient hyperglycaemia in early pregnancy results in (1) increased placental growth and (2) an up-regulation of placental nutrient transport capacity, which leads to fetal overgrowth at term. In order to test this hypothesis, pregnant rats were given intraperitoneal injections of glucose (2 g kg(-1), resulting in a 50-100% increase in blood glucose level during 90 min) or saline (control) in either early or late gestation using four different protocols: one single injection on gestational day (GD) 10 (n=5), three injections on GD 10 (n=8-9), six injections on GD 10 and 11 (n=9-11) or three injections on GD 19 (n=7-8). Multiple injections were given approximately 4 h apart. Subsequently, animals were studied on GD 21. Three glucose injections in early pregnancy significantly increased placental weight by 10%, whereas fetal weight was found to be increased at term in response to both three (9% increase in fetal weight, P<0.05) and six glucose injections (7%, P=0.05) in early gestation. A single glucose injection on GD 10 or three injections of glucose on GD 19 had no effect on placental or fetal growth. In groups where a change in feto-placental growth was observed, we measured placental system A and glucose transport activity in the awake animals on GD 21 and placental expression of the glucose and amino acid transporters GLUT1, GLUT3, SNAT2 (system A), LAT1 and LAT 2 (system L). Placental system A transport at term was down-regulated by six glucose injections in early pregnancy (by -33%, P<0.05), whereas placental mRNA and protein levels were unchanged. No long-term alterations in maternal metabolic status were detected. In conclusion, we demonstrate that transient hyperglycaemia in early pregnancy is sufficient to increase fetal weight close to term. In contrast, brief hyperglycaemia in late pregnancy did not stimulate fetal growth. Increased fetal growth may be explained by a larger placenta, which would allow for more nutrients to be transferred to the fetus. These data suggest that maternal metabolic control in early pregnancy is an important determinant for feto-placental growth and placental function throughout the remainder of gestation. We speculate that maternal metabolism in early pregnancy represents a key environmental cue to which the placenta responds in order to match fetal growth rate with the available resources of the mother.

Undernutrition in utero augments systolic blood pressure and cardiac remodeling in adult mouse offspring: possible involvement of local cardiac angiotensin system in developmental origins of cardiovascular disease.

Evidence has emerged that undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. Recently, the local expression of angiotensinogen and related bioactive substances has been demonstrated to play a pivotal role in cardiac remodeling, i.e. fibrosis and hypertrophy. The aim of the present study was to clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders. We developed a mouse model of undernutrition in utero by maternal food restriction, in which offspring (UN offspring) showed an increase in systolic blood pressure (8 wk of age, P < 0.05; and 16 wk, P < 0.01), perivascular fibrosis of the coronary artery (16 wk, P < 0.05) and cardiac cardiomegaly (16 wk, P < 0.01), and cardiomyocyte enlargement, concomitant with a significant augmentation of angiotensinogen (P < 0.05) and endothelin-1 (P < 0.01) mRNA expression and a tendency to increase in immunostaining for both angiotensin II and endothelin-1 in the left ventricles (16 wk). These findings suggest that fetal undernutrition activated the local cardiac angiotensin system-associated bioactive substances, which contributed, at least partly, to the development of cardiac remodeling in later life, in concert with the effects of increase in blood pressure.

Effect of early nutrition on intestine development of intrauterine growth retardation in rats and its correlation to leptin.

AIM: To investigate the intestine and body development of intrauterine growth retardation (IUGR) rats under early different protein diet and to analyze the correlation between leptin and intestine and body development. METHODS: An IUGR rat model was established by food restriction of pregnant female rats. Fifty-six neonatal IUGR rats and 24 neonatal normal rats were randomly divided into normal control group (C group), IUGR model group (SC group), low protein diet IUGR group (SL group), and high protein diet IUGR group (SH group). Eight rats were killed per group at wk 0, 4, and 12. Serum leptin, body weight (BW), body length (BL), intestinal weight (IW), intestinal length (IL), and intestinal disaccharidase (including lactase, maltase, and saccharase) were detected. RESULTS: BW (4.50+/-0.41 g), BL (5.96+/-0.40 cm), IW (0.05+/-0.01 g), and IL (15.9+/-2.8 cm) in neonatal IUGR rats were much lower than those in C group (6.01+/-0.55 g, 6.26+/-0.44 cm, 0.10+/-0.02 g, 21.8+/-2.7 cm, P<0.05), while intestinal lactase and maltase activities were higher than those in C group. SH group showed the fastest catch up growth and their BW, BL, IW, and IL reached the C group level at wk 4. SC group showed relatively slower catch up growth than SH group, and their BW, BL, IW did not reach the C group level at wk 4. SL group did not show intestine and body catch up growth. Intestinal maltase (344+/-33 micromol/(min.g)) and saccharase activities (138+/-32 micromol/(min.g)) in SL group were both markedly lower than those in C group (751+/-102, 258+/-27 micromol/(min.g), P<0.05). There were no significant differences in lactase activities at wk 4 and disaccharidase activities at wk 12 among all groups (P>0.05). The leptin level in SL group (0.58+/-0.12 ng/mL) was the highest in all groups, and much lower in SH group (0.21+/-0.03 ng/mL) than that in any other IUGR groups at wk 4 (P<0.05). Leptin was negatively related to BW (r = -0.556, P = 0.001), IW (r = -0.692, P = 0.001) and IL (r = -0.738, P = 0.000) at wk 4, while no correlation was found at wk 12. CONCLUSION: High protein diet is a reasonable early nutritional mode to IUGR rats in promoting intestine and body catch up growth.

Maternal nutrient restriction reduces concentrations of amino acids and polyamines in ovine maternal and fetal plasma and fetal fluids.

Amino acids and polyamines are essential for placental and fetal growth, but little is known about their availability in the conceptus in response to maternal undernutrition. We hypothesized that maternal nutrient restriction reduces concentrations of amino acids and polyamines in the ovine conceptus. This hypothesis was tested in nutrient-restricted ewes between Days 28 and 78 (experiment 1) and between Days 28 and 135 (experiment 2) of gestation. In both experiments, ewes were assigned randomly on Day 28 of gestation to a control group fed 100% of National Research Council (NRC) nutrient requirements and to an nutrient-restricted group fed 50% of NRC requirements. Every 7 days beginning on Day 28 of gestation, ewes were weighed and rations adjusted for changes in body weight. On Day 78 of gestation, blood samples were obtained from the uterine artery and umbilical vein for analysis. In experiment 2, nutrient-restricted ewes on Day 78 of gestation either continued to be fed 50% of NRC requirements or were realimented to 100% of NRC requirements until Day 135. Fetal weight was reduced in nutrient-restricted ewes at both Day 78 (32%) and Day 135 (15%) compared with controls. Nutritional restriction markedly reduced (P < 0.05) concentrations of total alpha-amino acids (particularly serine, arginine-family amino acids, and branched-chain amino acids) and polyamines in maternal and fetal plasma and in fetal allantoic and amniotic fluids at both mid and late gestation. Realimentation of nutrient-restricted ewes increased (P < 0.05) concentrations of total alpha-amino acids and polyamines in all the measured compartments and prevented intrauterine growth retardation. These novel findings demonstrate that 50% global nutrient restriction decreases concentrations of amino acids and polyamines in the ovine conceptus that could adversely impact key fetal functions. The results have important implications for understanding the mechanisms responsible for both intrauterine growth retardation and developmental origins of adult disease.