99
Eurly Human Development, 29 (1992) 99-106 Elsevier Scientific Publishers Ireland Ltd.
EHD 01256
Metabolic aspects of fetal and neonatal growth Frederick C. Battaglia University
of Colorado
School
of Medicine,
4200 E. Ninth
Ave.
B-199.
Denver,
CO 80262
(USA)
This review covers the transplacental transport of amino acids to the fetus and the role of placental metabolism and fetal metabolism in the utilization of amino acids. Particular attention is paid to the non-essential amino acids and to their rates of production within the fetus or placenta. The supply of amino acids is compared with their requirements for accretion in protein and for their use as metabolic fuels. Recent studies of protein synthesis in relation to gestational age are also reviewed. Key words: fetal amino acids; fetal metabolism; placental amino acids; amino acid transport; placental metabolism
Introduction In this review, I should like to cover some of the new concepts which have emerged relating to fetal and placental metabolism. Because of the time constraints, I shall focus on just a few aspects of carbohydrate and amino acid metabolism. Studies of glucose metabolism One of the aspects of fetal metabolism which has now been well established is that the supply of glucose to the uterus is largely utilized within the utero-placental tissues, rather than by the fetus. Figure 1 presents the partition between fetus and utero-placenta in the late gestation fetal lamb [l]. Notice that as the supply of glucose to the uterus falls, the placental supply decreases proportionately. Recent studies by other investigators have served to reinforce this concept; [2,3] that with diminished glucose supply, the placenta must increase its utilization of other substrates as metabolic fuels. Conversely, as the glucose supply to the placenta from Correspondence to: Frederick C. Battaglia, University of Colorado School of Medicine, 4200 E. Ninth Ave. B-199, Denver, CO 80262, USA.
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
NOFIMOGLVCEMIA
(60.5 k.8 mgldl)
I mg/mh UTERO-PMXNtAt-1
87% 1
HVQ~LVCtlYlA
(34.2 f2.7
mg/dl)
Fig. 1. Fractional partition of maternal glucose production to non-uterine maternal tissues, uteroplacenta and fetus in normoglycemic sheep (first column) and hypoglycemic sheep (second column) (Ref. I).
the maternal circulation increases, there is increasing glucose oxidation leading to glucose sparing of other potential fuels. In mid-gestation the consumption of glucose by the utero-placental tissues represents 80-85% of total uterine consumption. There is an enormous increase in the placental capacity for glucose transport as gestation progresses. Figure 2, modified from the study of Molina et al. [4] illustrates the increasing placental glucose transport capacity and further illustrates the fact that most of the increase is due to a change within the placenta, presumably by increasing the number of glucose transporter proteins per cell or the total cellular surface area. In human pregnancies studied at the time of cordocentesis, we have been able to demonstrate a decreased glucose gradient across the placenta, compared to late gestation [5]. Thus, in man as in sheep, one factor contributing to the increased glucose transport with increasing gestational age is the increased transplacental glucose gradient. In man the decreased gradient in mid-gestation leads to a reversal of the normal fetal-maternal glucose gradient between maternal blood and fetal um-
101
20 E (u
PLACENTAL GLUCOSE TRANSFER (Spontaneous vs. Fixed A-a Glucose Gradient
?3l -5
135 d
OLD 5’ 5 3 $0 0’
-
spontaneaua
3
-K-
Fixed at 45 mp%
(3 5” ‘Z .-
70°80
90 100 110 120 130 140 Gestational Age (d)
Fig. 2. Umbilical glucose uptake versus gestational age in the fetal lamb from mid to late gestation. Data marked by X equals umbilical glucose uptake when the transplacental glucose gradient is fixed at 45%.
bilical venous blood when maternal glucose concentration found in late gestation (Fig. 3).
is reduced. This is never
Amino acid metabolism To turn now to amino acid metabolism: the supply of amino acids to a rapidly growing fetus or newborn infant is crucial to meet the requirements for net protein accretion. In addition, amino acids may play critical roles as metabolic fuels for certain tissues such as the GI tract. To the extent that amino acids are oxidized, their requirements are increased beyond those essential for protein synthesis. In recent years, there has been more attention paid to the relationship between amino acid intake, primarily as protein in milk feedings and the growth and well being of newborn infants. This review focuses on an earlier stage of development, that of fetal life in the latter half of gestation and it will consider the relationship between amino acid supply to the fetus and fetal amino acid requirements. This topic is important to neonatal medicine as well as to maternal and fetal physiology. For neonatal medicine, it provides an important reference point to estimate amino acid requirements in very low birth weight premature infants. Knowledge of fetal amino acid supply and metabolism is important to neonatologists for another reason, namely it provides important insight into key questions to be answered about neonatal amino acid metabolism. Some of the unique features of fetal amino acid metabolism may persist in the immediate newborn period, particularly in premature infants. Neonatologists can then design metabolic research protocols to determine
102
Fig. 3. (A) Relationship between fetal and maternal glucose concentrations in all 14 cases (y = 2.08 + O.NKD, r = 0.92, P < 0.001). (B) Relationship between fetal and maternal glucose concentrations when maternal concentration > 4.44 mmol/l (y = 1.14 + 0.72x; r = 0.97, P < 0.001) (---). An identity line is also presented for reference.
whether the unique features of fetal amino acid metabolism persist in the neonatal period as well. If these features persist, they may influence amino acid requirements. While the accretion rate of amino acids during fetal life is known in several species [6,7], the delivery rate of amino acids to the fetus from the placenta (the umbilical uptake of amino acids) is only known for the fetal lamb. Recently we have been able
103
to study the mid-gestation fetus under chronic steady state conditions. At this stage of gestation a fetal lamb which will be 4 kg at birth, is approximately 200 g and the placenta 500 g [8,9]. These studies have shown some features of amino acid supply which are similar to those at term. For example, the uptake of most neutral amino acids exceeds their rates of accretion. Given this finding, it is not surprising that there is a very high urea production rate in the mid-gestation fetus since excess amino acids are available for oxidation. Also, just as is the case in late gestation, the acidic amino acids aspartate and glutamate are not entering the fetal circulation. In fact, there is a net loss of glutamate from the fetal circulation into the placenta [lo]. The most striking difference from late gestation, is the large uptake of serine by the placenta from the fetal circulation. It is clear that at mid-gestation the fetus must synthesize serine to meet fetal requirements at a relatively high rate. Overall the uptake of nitrogen from amino acids per gram fetal weight at mid gestation is four times higher than at term. Interorgan transport of amino acids between the fetal liver and placenta The placenta delivers a supply of amino acids to the fetus in both mid and late gestation which exceeds the requirements for net protein accretion [ 111. The fetal liver is perfused primarily by umbilical venous blood and extracts most amino acids from the blood in large amounts. Some amino acids are released from the fetal liver into the circulation. These include glutamate and serine. In contrast to most other amino acids, these amino acids do not exit the placenta into the umbilical circulation. Glutamate is taken up from the fetal circulation into the placenta whereas serine has no net flux between the fetal circulation and the placenta in late gestation. At mid gestation, it too is taken up by the placenta. The amino acids which can give rise to glutamate and serine, glutamine and glycine are taken up from the placenta and delivered to the fetal liver. These combined observations suggest the possibility that there is interorgan cycling of these metabolically related pairs between the two organs, the placenta and fetal liver [12]. Studies of leucine metabolism The use of multiple carbon tracers, such as [‘4C]leucine and [‘3C]leucine, has proven useful in defining the metabolism of amino acids in the fetal vs. placental compartments. In a series of studies [ 13- 151 we have examined leucine fluxes in the fetal lamb from mid- to late-gestation. Given the fact that leucine is an essential amino acid, some of the findings were somewhat surprising. First of all, there is a relatively high rate of oxidation of leucine in the fetus, with an oxidation fraction of approximately 25% leucine oxidation is confined to the fetus, with no appreciable oxidation in the placenta. On the other hand, leucine is not simply transported across the placenta, but a significant fraction is deaminated within the placenta and its deamination product, alpha-keto-isocaproic acid (UC) is delivered into both the uterine and umbilical circulations. Almost 40% of the tracer leucine infused into the fetal circulation leaves the fetus and enters the placenta. Most of the leucine entering the placenta remains there, with very little entering the maternal circulation. Thus, even essential amino acids may be metabolized within the placenta and may be used within the fetus as metabolic fuels. Obviously it would be crucial for the fetus to turn
104
off the oxidation of essential amino acids under those conditions where their supply to the fetus may be limited such as with intrauterine growth retardation (IUGR). Studies of glycine metabolism
The observations of a net uptake of glycine by the fetal liver associated with a net efIIux of serine prompted studies of glycine metabolism in late gestation fetal lambs which had both the hepatic venous and umbilical venous circulations chronically catheterized [ 16). [ l-‘3C]glycine and [ 1- 14C]glycine were infused into the fetal circulation for 3-5 h to ensure both steady state enrichments and specific activities of glycine in the fetal circulation. Glycine fluxes were then measured into and out of the placenta and fetal liver. In contrast to leucine, there is little placental uptake of tracer glycine from the fetal circulation. The oxidation fraction of glycine was approximately 12% and this was confined to the fetus, with no evidence of placental oxidation. The fetal liver had a net uptake of tracer glycine and net efflux of both tracer-labelled COz and serine. Glycine oxidation in the fetal liver accounted for 70% of total fetal glycine oxidation. Clearly, the fetal liver is a major site of glycine oxidation and accounts for some of the serine production from glycine. In summary, glycine, a non-essential amino acid demonstrates that a crucial aspect of its supply to meet fetal requirements is represented by its production, either in the fetal or placental compartments. It also brings out the fact that amino acids entering the fetal circulation may not be derived from the maternal plasma pool; i.e. they may be synthesized from other compounds within the placenta. Figure 4 summarizes some of the pathways of placental metabolism which have already been identified. Whether in any given fetus the production rate is adequate to meet requirements is unknown, but certainly the possibility that such amino acids may be ‘semi-essential’ exists. If their production rates were inadequate, the supply to meet protein synthetic requirement may become limiting upon fetal growth. In this regard, the question of whether some non-essential amino acids are indeed required in the dietary supply in appreciable amounts, is similar to the questions which have been raised regarding glycine requirements in the newborn and premature infant. There too, it has been suggested that glycine might in fact be required in the diet in increased amounts under certain circumstances, because endogenous glycine production might be inadequate. In fact, this is an area that deserves study for all of the ‘non-essential’ amino acids. One cannot assume that their endogenous production rates are adequate under all conditions. The question of whether their production rates in early development are adequate to meet requirements under conditions associated with fetal growth retardation, deserves further investigation. Conceptually these issues are not unlike similar concerns regarding rates of gluconeogenesis during development. Clinical studies of perinatal amino acid metabolism
The advent of cordocentesis or periumbilical blood sampling for a variety of clinical purposes has permitted us to design clinical studies utilizing this procedure. This can be a powerful clinical research tool since it permits biochemical measurements upon fetal blood, undistorted by the process of delivery. Previously the only access to fetal blood came at the time of parturition. The early studies we
105
have carried out confirmed that certain physiologic characteristics described in the fetal lamb also applied to the human fetus. For example, there was a higher level of fetal oxygenation at mid-gestation than at term [ 171. Also there was clear evidence that the glucose concentration gradient across the placenta increased from mid-gestation until term [ 181. For amino acids, clinical studies have shown that total amino acid concentrations, especially branched chain amino acid concentrations, are reduced in the circulation of IUGR fetuses compared to normally grown fetuses [ 191. Since these lower concentrations can be found even at cordocentesis weeks before delivery [20], it is clearly not a transient phenomenon induced by the stress of labor and delivery. More recently we have begun to develop a research design permitting the evaiuation of placental transport of amino acids in IUGR and normal pregnancies. These studies have utilized the infusion of stable isotopically labelled amino acids into the maternal circulation prior to cordocentesis or elective cesarean section. Thus, the enrichments of the labelled amino acids in the fetal and maternal circulations can be compared. While we have only preliminary data, the striking differences in placental transport of leucine vs. glycine found in pregnant sheep, can also be demonstrated across the human placenta. It is our hypothesis that this approach can provide a good deal of information not only about relative rates of transport of amino acids across the placenta in vivo but also about fetal and placental metabolism of amino acids. References Hay, W.W., Sparks, J.W., Wilkening, R.B. et al. (1983): Partition of maternal glucose production between conceptus and maternal tissues in sheep. Am. J. Physiol., 245, E347-E350. DiGiacomo, J.E. and Hay, W.W., Jr. (1989): Regulation of placental glucose transfer and consumption by fetal glucose production. Pediatr. Res., 25, 429-434. Hay, W.W., Jr., Molina, R., DiGiacomo, J.E. et al. (1990): Model of placental glucose consumption and glucose transfer. Am. J. Physiol., 258, R569-R577. Molina, R.D., Meschia, G., Battaglia, F.C. et al. (1991): Gestational maturation of placental glucose transfer capacity in sheep. Am. J. Physiol., 261, R697-R704. Boxxetti, P., Ferrari, M., Marconi, A.M. et al. (1988): The relationship of maternal and fetal glucose concentrations in the human from mid gestation until term. Metabolism, 37, 358-363. Mier, P., Teng, C., Battaglia, F.C. et al. (1981): The rate of ammo acid nitrogen and total nitrogen accumulation in the fetal lamb. Proc. Sot. Exp. Biol. Med., 167, 463-468. Sparks, J.W., Girard, J.R., Callikan, S. et al. (1985): Growth of the fetal guinea pig: physical and chemical characteristics. Am. J. Physiol., 248, E132-E139. Bell, A.W., Kennaugh, J.M., Battaglia, F.C. et al. (1986): Metabolic and circulatory studies of the fetal lamb at mid gestation. Am. J. Physiol., 250, E538-E544. Bell, A.W., Battagha, F.C., Makowski, E.L. et al. (1985): Relationship between metabolic rate and body size in fetal liver. Biol. Neonate, 47, 120-123. Bell, A.W., Kennaugh, J.M., Battagha, F.C. et al. (1989): Uptake of amino acids and ammonia at mid gestation by the fetal lamb. Q. J. Exp. Physiol., 74, 635-643. Carter, B.S., Moores, R.R. and Battagha, F.C. (1991): A review of placental transport and fetal and placental metabolism of amino acids. J. Nutr. B&hem., 2, 4-13. Marconi, A.M., Battaglia, F.C., Meschia, G. et al. (1989): A comparison of amino acid arteriovenous differences across the liver, hindlimb and placenta in the fetal lamb. Am. J. Physiol., 257, E909-E915. 13 Kennaugh, J.M., Bell, A.W., Meschia, G. and Battaglia, F.C. (1987): Ontogenetic changes in protein synthesis rate and leucine oxidation rate during fetal life. Pediatr. Res., 22, 688-692.
106 14 vanVeen, L.C.P., Meschia, G., Hay, W.W., Jr. and Battaglia, F.C. (1987): Leucine disposal and oxidation rates in the fetal lamb. Metabolism, 36, 48-53. 15 Loy, G.L., Quick, A.N., Hay, W.W., Jr. et al. (1990): Feto-placental deamination and decarboxylation of leucine. Am. J. Physiol., 259 (Endocrinol. Metab. 22), E492-E497. 16 Cetin, I., Sparks, J.W., Quick, A.N. et al. (1990): Glycine turnover and oxidation and hepatic serine synthesis from glycine in fetal lambs. Am. J. Physiol., in press. 17 Bozzetti, P., Buscaglia, M., Cetin, I. et al. (1987): Respiratory gases, acid-base balance and lactate concentrations in the mid-term human fetus. Biol. Neonate, 51, 188-197. 18 Bozzetti, P., Ferrari, M.M., Marconi, A.M. et al. (1988): The relationship of maternal and fetal glucose concentrations in the human from mid gestation until term. Metabolism, 37, 358-363. 19 Cetin, I., Marconi, A.M., Bozzetti, P. et al. (1988): Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am. J. Obstet. Gynecol., 158, 120-126. 20 Cetin, I., Corbetta, C., Sereni, L.P. et al. (1990): Umbilical amino acid concentrations in normal and growth retarded fetuses sampled in utero by cordocentesis. Am. J. Obstet. Gynecol., 162, 253-261.
Eurly Human Development, 29 (1992) 99-106 Elsevier Scientific Publishers Ireland Ltd.
EHD 01256
Metabolic aspects of fetal and neonatal growth Frederick C. Battaglia University
of Colorado
School
of Medicine,
4200 E. Ninth
Ave.
B-199.
Denver,
CO 80262
(USA)
This review covers the transplacental transport of amino acids to the fetus and the role of placental metabolism and fetal metabolism in the utilization of amino acids. Particular attention is paid to the non-essential amino acids and to their rates of production within the fetus or placenta. The supply of amino acids is compared with their requirements for accretion in protein and for their use as metabolic fuels. Recent studies of protein synthesis in relation to gestational age are also reviewed. Key words: fetal amino acids; fetal metabolism; placental amino acids; amino acid transport; placental metabolism
Introduction In this review, I should like to cover some of the new concepts which have emerged relating to fetal and placental metabolism. Because of the time constraints, I shall focus on just a few aspects of carbohydrate and amino acid metabolism. Studies of glucose metabolism One of the aspects of fetal metabolism which has now been well established is that the supply of glucose to the uterus is largely utilized within the utero-placental tissues, rather than by the fetus. Figure 1 presents the partition between fetus and utero-placenta in the late gestation fetal lamb [l]. Notice that as the supply of glucose to the uterus falls, the placental supply decreases proportionately. Recent studies by other investigators have served to reinforce this concept; [2,3] that with diminished glucose supply, the placenta must increase its utilization of other substrates as metabolic fuels. Conversely, as the glucose supply to the placenta from Correspondence to: Frederick C. Battaglia, University of Colorado School of Medicine, 4200 E. Ninth Ave. B-199, Denver, CO 80262, USA.
0378-3782/92/$05.00 0 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland
NOFIMOGLVCEMIA
(60.5 k.8 mgldl)
I mg/mh UTERO-PMXNtAt-1
87% 1
HVQ~LVCtlYlA
(34.2 f2.7
mg/dl)
Fig. 1. Fractional partition of maternal glucose production to non-uterine maternal tissues, uteroplacenta and fetus in normoglycemic sheep (first column) and hypoglycemic sheep (second column) (Ref. I).
the maternal circulation increases, there is increasing glucose oxidation leading to glucose sparing of other potential fuels. In mid-gestation the consumption of glucose by the utero-placental tissues represents 80-85% of total uterine consumption. There is an enormous increase in the placental capacity for glucose transport as gestation progresses. Figure 2, modified from the study of Molina et al. [4] illustrates the increasing placental glucose transport capacity and further illustrates the fact that most of the increase is due to a change within the placenta, presumably by increasing the number of glucose transporter proteins per cell or the total cellular surface area. In human pregnancies studied at the time of cordocentesis, we have been able to demonstrate a decreased glucose gradient across the placenta, compared to late gestation [5]. Thus, in man as in sheep, one factor contributing to the increased glucose transport with increasing gestational age is the increased transplacental glucose gradient. In man the decreased gradient in mid-gestation leads to a reversal of the normal fetal-maternal glucose gradient between maternal blood and fetal um-
101
20 E (u
PLACENTAL GLUCOSE TRANSFER (Spontaneous vs. Fixed A-a Glucose Gradient
?3l -5
135 d
OLD 5’ 5 3 $0 0’
-
spontaneaua
3
-K-
Fixed at 45 mp%
(3 5” ‘Z .-
70°80
90 100 110 120 130 140 Gestational Age (d)
Fig. 2. Umbilical glucose uptake versus gestational age in the fetal lamb from mid to late gestation. Data marked by X equals umbilical glucose uptake when the transplacental glucose gradient is fixed at 45%.
bilical venous blood when maternal glucose concentration found in late gestation (Fig. 3).
is reduced. This is never
Amino acid metabolism To turn now to amino acid metabolism: the supply of amino acids to a rapidly growing fetus or newborn infant is crucial to meet the requirements for net protein accretion. In addition, amino acids may play critical roles as metabolic fuels for certain tissues such as the GI tract. To the extent that amino acids are oxidized, their requirements are increased beyond those essential for protein synthesis. In recent years, there has been more attention paid to the relationship between amino acid intake, primarily as protein in milk feedings and the growth and well being of newborn infants. This review focuses on an earlier stage of development, that of fetal life in the latter half of gestation and it will consider the relationship between amino acid supply to the fetus and fetal amino acid requirements. This topic is important to neonatal medicine as well as to maternal and fetal physiology. For neonatal medicine, it provides an important reference point to estimate amino acid requirements in very low birth weight premature infants. Knowledge of fetal amino acid supply and metabolism is important to neonatologists for another reason, namely it provides important insight into key questions to be answered about neonatal amino acid metabolism. Some of the unique features of fetal amino acid metabolism may persist in the immediate newborn period, particularly in premature infants. Neonatologists can then design metabolic research protocols to determine
102
Fig. 3. (A) Relationship between fetal and maternal glucose concentrations in all 14 cases (y = 2.08 + O.NKD, r = 0.92, P < 0.001). (B) Relationship between fetal and maternal glucose concentrations when maternal concentration > 4.44 mmol/l (y = 1.14 + 0.72x; r = 0.97, P < 0.001) (---). An identity line is also presented for reference.
whether the unique features of fetal amino acid metabolism persist in the neonatal period as well. If these features persist, they may influence amino acid requirements. While the accretion rate of amino acids during fetal life is known in several species [6,7], the delivery rate of amino acids to the fetus from the placenta (the umbilical uptake of amino acids) is only known for the fetal lamb. Recently we have been able
103
to study the mid-gestation fetus under chronic steady state conditions. At this stage of gestation a fetal lamb which will be 4 kg at birth, is approximately 200 g and the placenta 500 g [8,9]. These studies have shown some features of amino acid supply which are similar to those at term. For example, the uptake of most neutral amino acids exceeds their rates of accretion. Given this finding, it is not surprising that there is a very high urea production rate in the mid-gestation fetus since excess amino acids are available for oxidation. Also, just as is the case in late gestation, the acidic amino acids aspartate and glutamate are not entering the fetal circulation. In fact, there is a net loss of glutamate from the fetal circulation into the placenta [lo]. The most striking difference from late gestation, is the large uptake of serine by the placenta from the fetal circulation. It is clear that at mid-gestation the fetus must synthesize serine to meet fetal requirements at a relatively high rate. Overall the uptake of nitrogen from amino acids per gram fetal weight at mid gestation is four times higher than at term. Interorgan transport of amino acids between the fetal liver and placenta The placenta delivers a supply of amino acids to the fetus in both mid and late gestation which exceeds the requirements for net protein accretion [ 111. The fetal liver is perfused primarily by umbilical venous blood and extracts most amino acids from the blood in large amounts. Some amino acids are released from the fetal liver into the circulation. These include glutamate and serine. In contrast to most other amino acids, these amino acids do not exit the placenta into the umbilical circulation. Glutamate is taken up from the fetal circulation into the placenta whereas serine has no net flux between the fetal circulation and the placenta in late gestation. At mid gestation, it too is taken up by the placenta. The amino acids which can give rise to glutamate and serine, glutamine and glycine are taken up from the placenta and delivered to the fetal liver. These combined observations suggest the possibility that there is interorgan cycling of these metabolically related pairs between the two organs, the placenta and fetal liver [12]. Studies of leucine metabolism The use of multiple carbon tracers, such as [‘4C]leucine and [‘3C]leucine, has proven useful in defining the metabolism of amino acids in the fetal vs. placental compartments. In a series of studies [ 13- 151 we have examined leucine fluxes in the fetal lamb from mid- to late-gestation. Given the fact that leucine is an essential amino acid, some of the findings were somewhat surprising. First of all, there is a relatively high rate of oxidation of leucine in the fetus, with an oxidation fraction of approximately 25% leucine oxidation is confined to the fetus, with no appreciable oxidation in the placenta. On the other hand, leucine is not simply transported across the placenta, but a significant fraction is deaminated within the placenta and its deamination product, alpha-keto-isocaproic acid (UC) is delivered into both the uterine and umbilical circulations. Almost 40% of the tracer leucine infused into the fetal circulation leaves the fetus and enters the placenta. Most of the leucine entering the placenta remains there, with very little entering the maternal circulation. Thus, even essential amino acids may be metabolized within the placenta and may be used within the fetus as metabolic fuels. Obviously it would be crucial for the fetus to turn
104
off the oxidation of essential amino acids under those conditions where their supply to the fetus may be limited such as with intrauterine growth retardation (IUGR). Studies of glycine metabolism
The observations of a net uptake of glycine by the fetal liver associated with a net efIIux of serine prompted studies of glycine metabolism in late gestation fetal lambs which had both the hepatic venous and umbilical venous circulations chronically catheterized [ 16). [ l-‘3C]glycine and [ 1- 14C]glycine were infused into the fetal circulation for 3-5 h to ensure both steady state enrichments and specific activities of glycine in the fetal circulation. Glycine fluxes were then measured into and out of the placenta and fetal liver. In contrast to leucine, there is little placental uptake of tracer glycine from the fetal circulation. The oxidation fraction of glycine was approximately 12% and this was confined to the fetus, with no evidence of placental oxidation. The fetal liver had a net uptake of tracer glycine and net efflux of both tracer-labelled COz and serine. Glycine oxidation in the fetal liver accounted for 70% of total fetal glycine oxidation. Clearly, the fetal liver is a major site of glycine oxidation and accounts for some of the serine production from glycine. In summary, glycine, a non-essential amino acid demonstrates that a crucial aspect of its supply to meet fetal requirements is represented by its production, either in the fetal or placental compartments. It also brings out the fact that amino acids entering the fetal circulation may not be derived from the maternal plasma pool; i.e. they may be synthesized from other compounds within the placenta. Figure 4 summarizes some of the pathways of placental metabolism which have already been identified. Whether in any given fetus the production rate is adequate to meet requirements is unknown, but certainly the possibility that such amino acids may be ‘semi-essential’ exists. If their production rates were inadequate, the supply to meet protein synthetic requirement may become limiting upon fetal growth. In this regard, the question of whether some non-essential amino acids are indeed required in the dietary supply in appreciable amounts, is similar to the questions which have been raised regarding glycine requirements in the newborn and premature infant. There too, it has been suggested that glycine might in fact be required in the diet in increased amounts under certain circumstances, because endogenous glycine production might be inadequate. In fact, this is an area that deserves study for all of the ‘non-essential’ amino acids. One cannot assume that their endogenous production rates are adequate under all conditions. The question of whether their production rates in early development are adequate to meet requirements under conditions associated with fetal growth retardation, deserves further investigation. Conceptually these issues are not unlike similar concerns regarding rates of gluconeogenesis during development. Clinical studies of perinatal amino acid metabolism
The advent of cordocentesis or periumbilical blood sampling for a variety of clinical purposes has permitted us to design clinical studies utilizing this procedure. This can be a powerful clinical research tool since it permits biochemical measurements upon fetal blood, undistorted by the process of delivery. Previously the only access to fetal blood came at the time of parturition. The early studies we
105
have carried out confirmed that certain physiologic characteristics described in the fetal lamb also applied to the human fetus. For example, there was a higher level of fetal oxygenation at mid-gestation than at term [ 171. Also there was clear evidence that the glucose concentration gradient across the placenta increased from mid-gestation until term [ 181. For amino acids, clinical studies have shown that total amino acid concentrations, especially branched chain amino acid concentrations, are reduced in the circulation of IUGR fetuses compared to normally grown fetuses [ 191. Since these lower concentrations can be found even at cordocentesis weeks before delivery [20], it is clearly not a transient phenomenon induced by the stress of labor and delivery. More recently we have begun to develop a research design permitting the evaiuation of placental transport of amino acids in IUGR and normal pregnancies. These studies have utilized the infusion of stable isotopically labelled amino acids into the maternal circulation prior to cordocentesis or elective cesarean section. Thus, the enrichments of the labelled amino acids in the fetal and maternal circulations can be compared. While we have only preliminary data, the striking differences in placental transport of leucine vs. glycine found in pregnant sheep, can also be demonstrated across the human placenta. It is our hypothesis that this approach can provide a good deal of information not only about relative rates of transport of amino acids across the placenta in vivo but also about fetal and placental metabolism of amino acids. References Hay, W.W., Sparks, J.W., Wilkening, R.B. et al. (1983): Partition of maternal glucose production between conceptus and maternal tissues in sheep. Am. J. Physiol., 245, E347-E350. DiGiacomo, J.E. and Hay, W.W., Jr. (1989): Regulation of placental glucose transfer and consumption by fetal glucose production. Pediatr. Res., 25, 429-434. Hay, W.W., Jr., Molina, R., DiGiacomo, J.E. et al. (1990): Model of placental glucose consumption and glucose transfer. Am. J. Physiol., 258, R569-R577. Molina, R.D., Meschia, G., Battaglia, F.C. et al. (1991): Gestational maturation of placental glucose transfer capacity in sheep. Am. J. Physiol., 261, R697-R704. Boxxetti, P., Ferrari, M., Marconi, A.M. et al. (1988): The relationship of maternal and fetal glucose concentrations in the human from mid gestation until term. Metabolism, 37, 358-363. Mier, P., Teng, C., Battaglia, F.C. et al. (1981): The rate of ammo acid nitrogen and total nitrogen accumulation in the fetal lamb. Proc. Sot. Exp. Biol. Med., 167, 463-468. Sparks, J.W., Girard, J.R., Callikan, S. et al. (1985): Growth of the fetal guinea pig: physical and chemical characteristics. Am. J. Physiol., 248, E132-E139. Bell, A.W., Kennaugh, J.M., Battaglia, F.C. et al. (1986): Metabolic and circulatory studies of the fetal lamb at mid gestation. Am. J. Physiol., 250, E538-E544. Bell, A.W., Battagha, F.C., Makowski, E.L. et al. (1985): Relationship between metabolic rate and body size in fetal liver. Biol. Neonate, 47, 120-123. Bell, A.W., Kennaugh, J.M., Battagha, F.C. et al. (1989): Uptake of amino acids and ammonia at mid gestation by the fetal lamb. Q. J. Exp. Physiol., 74, 635-643. Carter, B.S., Moores, R.R. and Battagha, F.C. (1991): A review of placental transport and fetal and placental metabolism of amino acids. J. Nutr. B&hem., 2, 4-13. Marconi, A.M., Battaglia, F.C., Meschia, G. et al. (1989): A comparison of amino acid arteriovenous differences across the liver, hindlimb and placenta in the fetal lamb. Am. J. Physiol., 257, E909-E915. 13 Kennaugh, J.M., Bell, A.W., Meschia, G. and Battaglia, F.C. (1987): Ontogenetic changes in protein synthesis rate and leucine oxidation rate during fetal life. Pediatr. Res., 22, 688-692.
106 14 vanVeen, L.C.P., Meschia, G., Hay, W.W., Jr. and Battaglia, F.C. (1987): Leucine disposal and oxidation rates in the fetal lamb. Metabolism, 36, 48-53. 15 Loy, G.L., Quick, A.N., Hay, W.W., Jr. et al. (1990): Feto-placental deamination and decarboxylation of leucine. Am. J. Physiol., 259 (Endocrinol. Metab. 22), E492-E497. 16 Cetin, I., Sparks, J.W., Quick, A.N. et al. (1990): Glycine turnover and oxidation and hepatic serine synthesis from glycine in fetal lambs. Am. J. Physiol., in press. 17 Bozzetti, P., Buscaglia, M., Cetin, I. et al. (1987): Respiratory gases, acid-base balance and lactate concentrations in the mid-term human fetus. Biol. Neonate, 51, 188-197. 18 Bozzetti, P., Ferrari, M.M., Marconi, A.M. et al. (1988): The relationship of maternal and fetal glucose concentrations in the human from mid gestation until term. Metabolism, 37, 358-363. 19 Cetin, I., Marconi, A.M., Bozzetti, P. et al. (1988): Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am. J. Obstet. Gynecol., 158, 120-126. 20 Cetin, I., Corbetta, C., Sereni, L.P. et al. (1990): Umbilical amino acid concentrations in normal and growth retarded fetuses sampled in utero by cordocentesis. Am. J. Obstet. Gynecol., 162, 253-261.
