Fetal Plasma Amino Acid Research Articles

IGF-1 infusion to fetal sheep increases organ growth but not by stimulating nutrient transfer to the fetus.

Insulin-like growth factor-1 (IGF-1) is an important fetal growth factor. However, the role of fetal IGF-1 in increasing placental blood flow, nutrient transfer, and nutrient availability to support fetal growth and protein accretion is not well understood. Catheterized fetuses from late gestation pregnant sheep received an intravenous infusion of LR3 IGF-1 (LR3 IGF-1; n = 8) or saline (SAL; n = 8) for 1 wk. Sheep then underwent a metabolic study to measure uterine and umbilical blood flow, nutrient uptake rates, and fetal protein kinetic rates. By the end of the infusion, fetal weights were not statistically different between groups (SAL: 3.260 ± 0.211 kg, LR3 IGF-1: 3.682 ± 0.183; P = 0.15). Fetal heart, adrenal gland, and spleen weights were higher (P < 0.05), and insulin was lower in LR3 IGF-1 (P < 0.05). Uterine and umbilical blood flow and umbilical uptake rates of glucose, lactate, and oxygen were similar between groups. Umbilical amino acid uptake rates were lower in LR3 IGF-1 (P < 0.05) as were fetal concentrations of multiple amino acids. Fetal protein kinetic rates were similar. LR3 IGF-1 skeletal muscle had higher myoblast proliferation (P < 0.05). In summary, LR3 IGF-1 infusion for 1 wk into late gestation fetal sheep increased the weight of some fetal organs. However, because umbilical amino acid uptake rates and fetal plasma amino acid concentrations were lower in the LR3 IGF-1 group, we speculate that animals treated with LR3 IGF-1 can efficiently utilize available nutrients to support organ-specific growth in the fetus rather than by stimulating placental blood flow or nutrient transfer to the fetus.NEW & NOTEWORTHY After a 1-wk infusion of LR3 IGF-1, late gestation fetal sheep had lower umbilical uptake rates of amino acids, lower fetal arterial amino acid and insulin concentrations, and lower fetal oxygen content; however, LR-3 IGF-1-treated fetuses were still able to effectively utilize the available nutrients and oxygen to support organ growth and myoblast proliferation.

Maternal supplementation with citrulline or arginine during gestation impacts fetal amino acid availability in a model of intrauterine growth restriction (IUGR).

Supplementing maternal diet with citrulline or arginine during gestation was shown to enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction in the rat. The aims of this study were to determine in the same model whether maternal supplementation with citrulline or arginine would increase 1) citrulline and arginine concentration in fetal circulation; 2) the expression of placental amino acid transporters, and 3) the fetal availability of essential amino acids. Pregnant rats (n=8 per group) were fed either an isocaloric control (20% protein, NP) or a low protein (LP, 4% protein) diet, either alone or supplemented with 2g/kg/d of l-citrulline (LP+CIT) or isonitrogenous Arginine (LP+ARG) in drinking water throughout gestation. Fetuses were extracted by C-section on the 21st day of gestation. The gene expression of system A (Slc38a1, Slc38a2, and Slc38a4) and L (Slc7a2, Slc7a5, Slc7a8) amino acid transporters was measured in placenta and amino acid concentrations determined in maternal and fetal plasma. Maternal LP diet decreased fetal (4.01±0.03 vs. 5.45±0.07g, p<0.0001) and placental weight (0.617±0.01 vs. 0.392±0.04g, p<0.001), by 26 and 36% respectively, compared with NP diet. Supplementation with either CIT or ARG increased fetal birth weight by≈5 or 11%, respectively (4.21±0.05 and 4.48±0.05g vs. 4.01±0.03g, p<0.05). CIT supplementation produced a 5- and 2-fold increase in fetal plasma citrulline and arginine, respectively, whereas ARG supplementation only increased fetal arginine concentration. LP diet led to lower placental SNAT 4 mRNA, and higher LAT2 and SNAT1 expression, compared with NP. SNAT4, 4hFC, LAT2 mRNA were up-regulated in LP+CIT and LP+ARG group compared with the un-supplemented LP group. Higher level of LAT1 mRNA was also observed in the LP+CIT group than in the LP group (p<0.01). SNAT2 expression was unchanged in response to CIT or ARG supplementation. Fetal amino acid concentrations were decreased by LP diet, and were not restored by CIT or ARG supplementation. The current findings confirm supplementation with citrulline or arginine enhances fetal growth in a rat model of IUGR. They further suggest that: 1) citrulline and arginine administered orally to the pregnant mother may reach fetal circulation; 2) citrulline effectively raises fetal arginine availability; and 3) although it failed to increase the concentrations of essential amino acids in fetal plasma, citrulline or arginine supplementation upregulates the gene expression of several placental amino acid transporters.

High-protein–low-carbohydrate diet during pregnancy alters maternal plasma amino acid concentration and placental amino acid extraction but not fetal plasma amino acids in pigs

A high protein-low-carbohydrate diet during pregnancy can cause intra-uterine growth restriction. However, its impact during pregnancy on maternal, umbilical and fetal plasma amino acid (AA) profiles is unknown. A maternal high-protein (30%)-low-carbohydrate (HP-LC) diet was compared with isoenergetic standard (12·1% crude protein; ST) and low-protein (6·5%)-high-carbohydrate (LP-HC) diets fed to nulliparous pregnant sows to examine changes in AA concentrations in maternal, venous and arterial umbilical and fetal plasma in mid and late pregnancy. At 64 and 94 days of pregnancy (dp), sows underwent Caesarean section, and maternal, umbilical and fetal plasma samples were collected. The HP-LC diet mainly affected maternal plasma AA concentrations. Plasma concentrations of Ile and Val were increased and those of Ala, Glu and Gly were decreased (P≤0·05) in HP-LC compared with ST sows at 64 and 94dp. The LP-HC diet decreased fetal plasma Glu concentration compared with the ST diet at 94dp. Substantial AA catabolism was reflected by increased (P≤0·05) maternal and fetal plasma urea concentrations with the HP-LC compared with the ST and LP-HC diets at 94dp. Fractional placental extraction of Val was higher whereas those of Ala, Gln and Glu were lower in the HP-LC compared with the ST sows at 64 and 94dp (P≤0·05). Reduced fetal mass at 94dp was accompanied by reduced fetal extraction of Lys and Pro in the HP-LC group (P≤0·05). In conclusion, a maternal HP-LC diet during pregnancy altered maternal plasma composition of many AA and modified placental AA extraction to compensate for imbalanced maternal nutrient intake.

Maternal Insulin-like Growth Factor-II Promotes Placental Functional Development Via the Type 2 IGF Receptor in the Guinea Pig

In guinea pigs, maternal insulin-like growth factor (IGF) infusion in early-pregnancy enhances placental transport near-term, increasing fetal growth and survival. The effects of IGF-II, but not IGF-I, appear due to enhanced placental labyrinthine (exchange) development. To determine if the type-2 IGF receptor (IGF2R) mediates these distinct actions of exogenous IGF-II in the mother, we compared the impact of IGF-II with an IGF-II analogue, Leu 27-IGF-II, which only binds the IGF2R. IGF-II, Leu 27-IGF-II (1 mg/kg per day.sc) or vehicle were infused from days 20–38 of pregnancy (term = 67 days) and placental structure and uptake and transfer of [ 3H]-methyl- d-glucose (MG) and [ 14C]-amino-isobutyric acid (AIB) and fetal growth and plasma metabolites, were measured on day 62. Both IGF-II and Leu 27-IGF-II increased the volume of placental labyrinth, trophoblast and maternal blood space within the labyrinth and total surface area of trophoblast for exchange, compared to vehicle. Leu 27-IGF-II also reduced the barrier to diffusion (trophoblast thickness) compared to vehicle and IGF-II. Both IGF-II and Leu 27-IGF-II increased fetal plasma amino acid concentrations and placental transfer of MG to the fetus compared to vehicle, with Leu 27-IGF-II also increasing AIB transport compared with vehicle and IGF-II. In addition, Leu 27-IGF-II increased fetal weight compared to vehicle. In conclusion, maternal treatment with IGF-II or Leu 27-IGF-II in early gestation, induce similar placental and fetal outcomes near term. This suggests that maternal IGF-II in early gestation acts in part via the IGF2R to persistently enhance placental functional development and nutrient delivery and promote fetal growth.

Modification of fetal plasma amino acid composition by placental amino acid exchangers in vitro

Fetal growth is dependent on both the quantity and relative composition of amino acids delivered to the fetal circulation, and impaired placental amino acid supply is associated with restricted fetal growth. Amino acid exchangers can alter the composition, but not the quantity, of amino acids in the intra- and extracellular amino acid pools. In the placenta, exchangers may be important determinants of the amino acid composition in the fetal circulation. This study investigates the substrate specificity of exchange between the placenta and the feto-placental circulation. Maternal-fetal transfer of radiolabelled amino acids and creatinine were measured in the isolated perfused human placental cotyledon. Transfer of L-[14C]serine or L-[14C]leucine, and [3H]glycine, were measured in the absence of amino acids in the fetal circulation (transfer by non-exchange mechanisms) and following 10-20 micromol boluses of unlabelled amino acids into the fetal circulation to provide substrates for exchange (transfer by exchange and non-exchange mechanisms). The ability of fetal arterial boluses of L-alanine and L-leucine to stimulate release of amino acids from the placenta was also determined using HPLC in order to demonstrate the overall pattern of amino acid release. Experiments with radiolabelled amino acids demonstrated increased maternal-fetal transfer of L-serine and L-leucine, but not glycine, following boluses of specific amino acids into the fetal circulation. L-[14C]Leucine, but not L-[14C]serine or [3H]glycine, was transferred from the maternal to the fetal circulation by non-exchange mechanisms also (P<0.01). HPLC analysis demonstrated that fetal amino acid boluses stimulated increased transport of a range of different amino acids by 4-7 micromol l(-1) (P<0.05). Amino acid exchange provides a mechanism to supply the fetus with amino acids that it requires for fetal growth. This study demonstrates that these transporters have the capacity to exchange micromolar amounts of specific amino acids, and suggests that they play an important role in regulating fetal plasma amino acid composition.

Maternal-fetal metabolism in normal pregnancy and preeclampsia

Adaptation to pregnancy in humans involves major anatomic, physiologic and metabolic changes in the mother in order to support and provide for the nutritional and metabolic needs of the growing conceptus. Metabolically, pregnancy is marked by several important and dynamic adjustments including increased insulin resistance, hyperlipidemia and changes in protein and amino acid metabolism. In general, these metabolic adaptations serve to increase nutrient availability for the benefit of the growing fetal-placental unit. Interestingly, the pregnancy complication preeclampsia is recognized to evidence biologic exaggerations of these normal metabolic adaptations of pregnancy. Specifically, preeclampsia is associated with increased insulin resistance, hypertriglyceridemia, high circulating free fatty acids, low high-density lipoprotein particles, and high maternal and fetal plasma amino acid concentrations. These metabolic alterations may contribute to the pathophysiology of the syndrome and may also influence fetal growth. The focus of this review will be to summarize the normal metabolic adaptations, transport and utilization of carbohydrates, lipids and amino acids that occur during pregnancy. Furthermore, we will review the differences in carbohydrate, lipid and amino acid metabolism in pregnancies complicated by preeclampsia in comparison to uncomplicated pregnancies.

Effects of Maternal Starvation on Hepatocyte Proliferation in the Late Gestation Fetal Rat

Fetal growth retardation, a common end point for a variety of conditions affecting mother and fetus, is associated with reduced liver mass. We have performed studies to determine the mechanism for decreased liver mass in a maternal starvation model of fetal growth restriction in the rat. Pregnant dams were deprived of food for 48 h before delivery on embryonic day 19 (E19). Fetal body weight was not affected. However, fetal liver weight was reduced by approximately 15%. Immunostaining of fetal liver for proliferating cell nuclear antigen and flow cytometry on isolated fetal hepatocytes showed G1 cell cycle arrest in samples from starved dams. Based on our prior studies showing attenuated hepatic insulin signaling in the late gestation fetal rat, we tested the hypothesis that G1 arrest in our model might be due to altered nutrient signaling. Fetal plasma amino acid analyses showed no decrease in branched-chain amino acids, but arginine concentrations were decreased in fetuses of fasted mothers. Reduced arginine in E19 fetal hepatocyte culture media was associated with decreased DNA synthesis. Whereas levels of cyclins D and E were unchanged in fetal hepatocytes exposed to low arginine, cyclin E-dependent kinase activity was reduced. Low arginine also induced changes in the translational machinery, indicative of impaired signaling through the nutrient sensing kinase mammalian target of rapamycin. Our results are consistent with the hypothesis that restricted nutrient availability signals to the hepatocyte cell cycle in fetuses of fasted mothers, thereby accounting for decreased hepatocyte proliferation and liver mass.

Effects of isulin-like growth factor-I on maternal and fetal plasma amino acid levels in pregnant rats.

Pregnant rats were subcutaneously administered with recombinant human insulin-like growth factor-I (rhIGF-I) in doses of 0 (control), 1, 2, and 4 microg/g body weight per day from day 18 to 21 of pregnancy. On day 21 of pregnancy, maternal and fetal plasma samples were collected and those amino acid levels were measured. The ratios of fetal/maternal plasma amino acids, especially leucine, isoleucine, tryptophan, phenylalanine and tyrosine, increased in 2 microg rhIGF-I treated group. Both total fetal weight and total placental weight were also higher than those in the control group. These results suggested that IGF-I enhanced fetal growth by, as one of its possible mechanisms, promoting placental amino acid supplies from the mother to fetuses.

Plasma amino acids in appropriate- and small-for-gestational-age fetuses

The fetal plasma amino acid profiles of 28 small-for-gestational-age fetuses were established in umbilical venous blood samples obtained by cordocentesis and the values were compared with those of 62 appropriate-for-gestational age fetuses. In the appropriate-for-gestational-age group fetal levels were significantly correlated with but were higher than the maternal levels, which indicates that amino acids are actively transported by the placenta. In the small-for-gestational-age group, the fetal plasma concentration and the fetomaternal ratio of essential amino acids was decreased and this decrease was significantly correlated with the degree of fetal hypoxemia. There was a variable response (e.g., alanine was increased, whereas serine and tyrosine were decreased) involved with nonessential amino acids. In umbilical venous hypoxemia the plasma ratio of nonessential /essential amino acids was increased, and the maternal plasma concentrations of both essential and nonessential amino acids were increased. These findings suggest that in uteroplacental insufficiency there is intrauterine starvation.

Umbilical amino acid concentrations in normal and growth-retarded fetuses sampled in utero by cordocentesis

Fetal plasma amino acid concentrations were obtained by cordocentesis at midgestation in 11 normal (appropriate for gestational age) fetuses and at late gestation in 12 small-for-gestational-age fetuses, and at cesarean section in 14 normal term infants. In normal fetuses total molar amino acid concentrations and fetal/maternal total molar concentration ratios did not change significantly between the second and third trimesters. Fetal and maternal concentrations of most amino acids were significantly correlated at both midgestation and late gestation. Small-for-gestational-age fetuses had significantly lower concentrations of total alpha-aminonitrogen; this was mainly because of a reduction of the branched chain amino acids valine, leucine, and isoleucine, and of lysine and serine. Maternal arterial concentrations of phenylalanine, arginine, histidine, and alanine were elevated in small-for-gestational-age pregnancies. Thus there are only minor changes in amino acid concentrations between midgestation and late gestation in normal fetuses with a constant fetal/maternal ratio. In small-for-gestational-age infants a significant reduction in alpha-aminonitrogen and in most essential amino acids was demonstrable in utero weeks before delivery.

Plasma amino acids in appropriate- and small-for-gestational-age fetuses

The fetal plasma amino acid profiles of 28 small-for-gestational-age fetuses were established in umbilical venous blood samples obtained by cordocentesis and the values were compared with those of 62 appropriate-for-gestational age fetuses. In the appropriate-for-gestational-age group fetal levels were significantly correlated with but were higher than the maternal levels, which indicates that amino acids are actively transported by the placenta. In the small-for-gestational-age group, the fetal plasma concentration and the fetomaternal ratio of essential amino acids was decreased and this decrease was significantly correlated with the degree of fetal hypoxemia. There was a variable response (e.g., alanine was increased, whereas serine and tyrosine were decreased) involved with nonessential amino acids. In umbilical venous hypoxemia the plasma ratio of nonessential/essential amino acids was increased, and the maternal plasma concentrations of both essential and nonessential amino acids were increased. These findings suggest that in uteroplacental insufficiency there is intrauterine starvation.

Concentrations of free amino acids in maternal and fetal plasma from conscious catheterised ewes during the last five weeks of pregnancy

Concentrations of amino acids, urea, glucose, fructose and corticosteroids were measured in maternal and fetal plasma from nine Scottish Blackface ewes during the last 35 days of pregnancy. During this period maternal plasma levels of most amino acids did not change significantly. In fetal plasma the concentrations of most amino acids decreased or remained relatively constant until about 20 days before birth (day -20) and then increased as term approached. Glucose levels in plasma from both sources did not change, but urea concentrations rose to maximum values about day -20. Except for valine and isoleucine, the concentrations of amino acids in fetal plasma varied independently of levels in maternal plasma up to day -20, but thereafter 10 amino acids, including seven essential amino acids, showed a significant positive correlation with maternal values. Possible causes of the observed variations in fetal plasma composition are discussed.

Free amino acid composition of human amniotic fluid at term.

SummaryPatterns of free amino acid concentrations in maternal venous plasma, umbilical arterial plasma, fetal urine, amniotic fluid and neonatal urine from eight infants delivered at term by elective Caesarean section before the onset of labour were determined. Concentrations of amino acids were in general greater in fetal plasma than in maternal plasma, amniotic fluid, fetal urine and neonatal urine. There was little correlation between amniotic fluid amino acid composition and the composition of fetal urine, fetal plasma or maternal plasma. Urine excreted during the first 24 hours after birth had a higher osmolality and greater amino acid concentrations than fetal urine in the bladder at the time of delivery. When compared with the urine in the bladder of fetuses delivered at 15 to 20 weeks, fetal urine at term has a lower osmolality and a different amino acid composition which is partially explained by reduced fetal plasma amino acid concentrations in later pregnancy and by alterations in the endogenous renal clearance of some amino acids.

Maternal and fetal plasma amino acid concentrations during gestation and in retarded fetal growth.

Maternal and fetal plasma amino acid concentrations during gestation and in retarded fetal growth.