- Email: [email protected]
Placental nutrient transfer and fetal growth
500
Jansson and Powell
Nutrition Volume 16, Numbers 7/8, 2000
Placental Nutrient Transfer and Fetal Growth Thomas Jansson, MD, PhD, and Theresa L. Powell, PhD From the Perinatal Center, Department of Physiology and Pharmacology, Go¨teborg University, Go¨teborg, Sweden INTRODUCTION The placenta represents the interface between the mother and fetus and delivers all the nutrients necessary for normal fetal growth and development. Consequently, fetal growth is intimately linked to the transport functions of the placenta. Two important pregnancy complications are associated with altered fetal-growth patterns. In intrauterine growth restriction (IUGR), the fetus fails to achieve its genetically determined growth potential and is born with a low birth weight for gestational age. In contrast, some fetuses of mothers with diabetes represent the other end of the growth spectrum in displaying signs of fetal overgrowth. Historically, the restricted growth in IUGR has been attributed to reduced placental blood flow, and the accelerated fetal growth in some diabetic pregnancies has been explained by maternal hyperglycemia. However, a growing body of evidence is now available suggesting that alterations in the activity and expression of placental nutrient transporters may contribute to the development of these pregnancy complications. In the human placenta there are two cell layers positioned between the maternal and fetal blood circulations: the syncytiotrophoblast and the fetal capillary endothelium. For the primary fetal nutrients, such as glucose and amino acids, the plasma membranes of the syncytiotrophoblast cell constitutes the main barrier for transplacental transport. The syncytiotrophoblast is a true syncytium with polarized plasma membranes: the microvillous membrane (MVM) faces the maternal blood and the basal membrane (BM) is adjacent to the fetal capillary. As in other epithelial cells, differences in the type, number and activity of transporters in these two plasma membranes of the syncytiotrophoblast provide the basis for vectorial transport of nutrients. Thus, isolation of MVM and BM and the subsequent study of these membrane fractions in vitro is a valuable strategy to assess placental transport functions of the human placenta.
PLACENTAL NUTRIENT TRANSPORT IN IUGR IUGR remains an important obstetric and pediatric problem and is associated with increased perinatal morbidity, higher incidence of neurodevelopmental impairment,1 and increased risk for a number of diseases in adulthood such as cardiovascular disease and diabetes.2,3 Plasma concentrations of glucose4 and certain amino acids5 are decreased in the IUGR fetus in utero, findings that have provided the rationale for studying placental transport systems for these nutrients in IUGR. Of the approximately 15 different transporters for amino acids in the human placenta, the Na⫹-dependent system A transporter has attracted the most attention. IUGR is associated with a marked decrease in the activity of system A in MVM,6 – 8 whereas information about BM is less abundant.8 More
Supported by the Swedish Medical Research Council (10838 and 11834), Frimurare-Barnhus-direktionen, the Åhlens Foundation, Willhelm & Martina Lundgrens Foundation, Torsten and Ragnar So¨derbergs Foundation, and the Swedish Diabetes Association. Correspondence to: Thomas Jansson, MD, PhD, Perinatal Center, Department of Physiology and Pharmacology, Go¨teborg University, Box 432, S-405 30 Go¨teborg, Sweden. E-mail: [email protected]
recently, the activity of transporters for essential amino acids has been studied in isolated syncytiotrophoblast plasma membranes. In IUGR, leucine uptake was shown to be decreased in both MVM and BM, whereas the uptake of lysine was reduced in BM only.9 Furthermore, the activity of the taurine transporter is reduced in MVM in association with IUGR.10 Transplacental transport of glucose in the human is a facilitated process and mediated primarily by the glucose transporter isoform-1 (GLUT-1).11 Although fetal hypoglycemia is common in IUGR, placental GLUT-1 activity and protein expression were found to be unaltered in this pregnancy complication.11
PLACENTAL NUTRIENT TRANSPORT IN PREGNANCIES COMPLICATED BY MATERNAL DIABETES In pregnancies complicated by maternal diabetes, fetal overgrowth still constitutes a significant clinical problem. The birth of a large-for-gestational-age baby represents a potential complication by the increased incidence of operative delivery and birth trauma such as shoulder dystocia.12 It has been hypothesized that maternal hyperglycemia in diabetes increases placental glucose transfer, resulting in fetal hyperglycemia and increased fetal insulin concentrations, which in turn stimulates fetal growth.13 However, even in diabetic pregnancies with strict glycemic control, fetal overgrowth is not uncommon,14 suggesting a complex relationship between metabolic derangement and fetal growth in maternal diabetes.15 The possibility exists that the poor correlation between maternal glycemic control in diabetes and the incidence of fetal overgrowth observed in many studies is related to alterations in placental glucose-transport characteristics. Compatible with this hypothesis, we reported an increased placental glucose-transporter protein expression and glucose-transport activity in BM in a group of patients with insulin-dependent diabetes (IDDM) delivering large-for-gestational-age infants at term.16 In contrast, placental glucose transporters were unaffected in gestational diabetes (GDM), whereas the activity of system A amino acid transporter in MVM appears to be increased in GDM (Jansson, Ekstrand, Wennergren, and Powell, unpublished data). These latter findings are in contrast to a study by Kuruvilla et al. who reported a reduced system-A activity in MVM isolated from diabetic pregnancies associated with fetal overgrowth.17 The reasons for the discrepant results of the two studies are not immediately apparent.
ALTERATIONS OF PLACENTAL TRANSPORTERS—A MECHANISM FOR REGULATING FETAL GROWTH? Whereas, for example, growth hormone affects fetal growth to a rather limited extent, fetal insulin and insulinlike growth factors (IGFs) have a pronounced effect on the pattern of fetal growth. Insulin stimulates the growth of most fetal tissues, with the exception of the brain, which is relatively insulin insensitive. In most cases of IUGR, growth restriction is “asymmetric,” with growth of the brain relatively spared and the growth of, e.g., skeletal muscle and liver severely restricted. Therefore, the low plasma levels of fetal insulin, characteristic for IUGR, may represent an important signal for the impaired growth. Similarly, fetal overgrowth in
Nutrition Volume 16, Numbers 7/8, 2000 maternal diabetes during pregnancy may be the consequence of fetal hyperinsulinemia, as originally suggested by Pedersen.13 Insulin is secreted from the fetal endocrine pancreas in response to amino acids and glucose, providing a direct and efficient coupling between plasma concentrations of major nutrients and fetal growth. It has generally been believed that decreased substrate supply to the placenta (impaired placental blood flow or maternal malnutrition causing IUGR) and increased supply of major nutrients (hyperglycemia in maternal diabetes resulting in fetal overgrowth) directly alter the nutrient levels in the fetal circulation. This model, however, does not account for changes in placental transport functions. We propose that the placenta, rather than functioning as a mere conduit for maternofetal nutrient fluxes, adapts its transport functions in response to changes in substrate supply. As a consequence, alterations in the expression or activity of placental transporters may serve as a mechanism for regulating fetal growth. More specifically, we have suggested that the downregulation of placental amino-acid–transport systems may be one of the signals altering fetal growth patterns in the face of a compromised supply line in cases of IUGR.9,10 In addition, increased activity of system-A transporters in GDM (Jansson, Ekstrand, Wennergren, and Powell, unpublished data) and increased BM GLUT-1 protein expression and activity in IDDM16 may explain the occurrence of fetal overgrowth in maternal diabetes despite rigorous control of maternal blood-glucose levels. The evidence for an active role for the placenta in the adaptation of fetal growth to changes in nutrient supply are largely indirect. The specific upregulation of placental system A and glucose transporters in GDM and IDDM, respectively, indicate that the placenta has a capacity to respond to some nutritional stimuli with a change in selective transport systems. Furthermore, the alterations in placental transport systems in IUGR are specific in the sense that, whereas the activity of some amino-acid transporters is reduced, other transport systems remain unchanged. This suggests that these alterations are not a result of a general “toxic” or degenerative effect on the placenta of the IUGR fetus. The actual etiology for the IUGR in these human studies were unknown, but a reduced placental blood flow (“placental insufficiency”) was likely to be a main contributor to the restricted fetal growth in most cases. Maternal malnutrition is not a major cause for restricted fetal growth in the industrialized world, but it remains a severe problem in developing countries. Placental transport functions in malnutrition have not been studied in the human but have been addressed in experimental models. In the pregnant rat it was found that protein malnutrition caused IUGR and a decrease in the activity of placental system-A transporter and of y⫹L and y⫹ systems for cationic amino acids, whereas system B0,⫹ and alanine, serine, and cysteine (ASC) were unaffected.18 Despite the differences in species and the cause of IUGR, these changes mirror the alterations found in the human studies. Interestingly, despite the severe reduction in protein intake, maternal plasma concentrations of amino acids were largely unchanged, suggesting that the downregulation of placental transporters mediated the restricted fetal growth.18 These animal experimental studies provide more direct support to the idea that the placenta monitors or senses maternal nutritional status or nutrient supply to the placenta and alters its transport functions accordingly.
HOW DOES THE PLACENTA MONITOR CHANGES IN NUTRIENT SUPPLY? If the placenta has the ability to adapt its transport functions in response to nutrient supply, the underlying mechanisms remain to be defined. In particular, the nature of the “receptor” involved is speculative. For example, is the monitored parameter one of the major nutrients itself (amino acids, glucose) or possibly something related more directly to blood supply (e.g., tissue oxygenation)? One possibility to consider is that hormonal pathways are in-
Placental Nutrient Transfer and Fetal Growth
501
volved. The placenta is a tremendously versatile endocrine organ in producing almost all known hormones and growth factors. Among many potential candidates involved in regulation of placental transporters is placental growth hormone (pGH), which is produced by the syncytiotrophoblast and secreted into the maternal circulation.19 Glucose has been shown to regulate the release of pGH,20 and circulating levels of pGH are decreased in IUGR.21 Furthermore, the effects of pGH are mediated, at least in part, by the release of IGF-1 from the liver.19 IGF-1 has been shown to regulate the trophoblast system-A transporter.22 Thus, it is possible that changes in nutrient supply to the placenta affect the activity of the placental system-A transporter mediated by pGH and IGF-1.
FUTURE DIRECTIONS FOR RESEARCH The study of placental nutrient transport is still in its infancy. Much of the research thus far has been descriptive in providing some of the information necessary to define the cellular mechanisms for transplacental transport. The findings that the activity and expression of placental transporters are altered in pregnancy complications clearly suggest that these transporters are subjected to regulation in vivo, and this will stimulate detailed studies of transporter regulation in the near future. A particularly challenging area will be to unravel the complex interactions between maternal nutrition, placental function, and fetal growth. This work will require an integrative approach employing a wide range of methods, from molecular biology to whole-animal physiology and experimental systems, such as isolated membranes, cells, and fragments, perfused cotyledons, and animal models representing several different species. Studies in pregnant women using recently developed stable isotope techniques will be valuable in the efforts to obtain a better understanding of the metabolism and transport of nutrients in vivo. The development of transgenic mice with genes encoding for nutrient transporters over- and underexpressed in the trophoblast would represent an important tool in future research in this area.
REFERENCES 1. Blair E, Stanley F. Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age. Am J Obstet Gynecol 1990;162:229 2. Hales CN, Barker DJP, Clark PMS, et al. Fetal and infant growth and impaired glucose tolerance at age 64. Br Med J 1991;303:1019 3. Barker DJP, Gluckman PD, Godfrey KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938 4. Economides DL, Nicolaides KH. Blood glucose and oxygen tension in smallfor-gestational-age fetuses. Am J Obstet Gynecol 1989;160:120 5. Cetin I, Marconi AM, Bozzetti P, et al. Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am J Obstet Gynecol 1988;158:120 6. Mahendran D, Donnai P, Glazier JD, et al. Amino acid (system A) transporter activity in microvillous membrane vesicles from the placentas of appropriate and small for gestational age babies. Pediatr Res 1993;34:661 7. Dicke JM, Henderson GI. Placental amino acid uptake in normal and complicated pregnancies. Am J Med Sci 1988;295:223 8. Dicke JM, Verges DK. Neutral amino acid uptake by microvillous and basal plasma membrane vesicles from appropriate- and small-for-gestational age human pregnancies. J Mater Fetal Med 1994;3:246 9. Jansson T, Scholtbach V, Powell TL. Placental transport of leucine and lysine is reduced in intrauterine growth restriction. Pediatr Res 1998;44:532 10. Norberg S, Powell TL, Jansson T. Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters. Pediatr Res 1998;44:233 11. Jansson T, Wennergren M, Illsley NP. Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. J Clin Endocrinol Metab 1993;77:1554 12. Casey BM, Lucas MJ, McIntire DD, Leveno KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90:869 13. Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol 1954;16:330
502
Prohaska
14. Garner P. Type I diabetes mellitus and pregnancy. Lancet 1995;346:157 15. Freinkel N. Of pregnancy and progeny. Diabetes 1980;29:1023–35 16. Jansson T, Wennergren M, Powell TL. Placental glucose transport and GLUT 1 expression in insulin dependent diabetes. Am J Obstet Gynecol 1999;180:163 17. Kuruvilla AG, D’Souza SW, Glazier JD, et al. Altered activity of the system A amino acid transporter in microvillous membrane vesicles from placentas of macrosomic babies born to diabetic women. J Clin Invest 1994;94:689 18. Malandro MS, Beveridge MJ, Kihlberg MS, Novak DA. Effect of low-protein diet-induced intrauterine growth retardation on rat placental amino acid transport. Am J Physiol 1996;271:C295
Nutrition Volume 16, Numbers 7/8, 2000 19. Alsat E, Guibourdenche J, Luton D, Frankenne F, Evain-Brion D. Human placental growth hormone. Am J Obstet Gynecol 1997;177:1526 20. Patel N, Alsat E, Igout A, et al. Glucose inhibits human placental GH secretion, in vitro. J Clin Endocrinol Metab 1995;80:1743 21. Mirlesse V, Frankenne F, Alsat E, et al. Placental growth hormone levels in pregnancies with intrauterine growth retardation. Pediatr Res 1993;34:439 22. Bloxam DL, Bax BE, Bax CMR. Epidermal growth factor and insulin-like growth factor I differentially influence the directional accumulation and transfer of 2-aminoisobutyrate (AIB) by human placental trophoblast in two-sided culture. Biochim Biophys Res Commun 1994;199:922
Long-Term Functional Consequences of Malnutrition During Brain Development: Copper Joseph R. Prohaska, PhD From the Department of Biochemistry and Molecular Biology, School of Medicine, University of Minnesota, Duluth, Minnesota, USA INTRODUCTION As we begin a new century, it seems clear that the future of our world will be dependent on the cognition and judgment shown by new leaders in making the most of the resources that exist on our planet. To develop that full cognition, a desirable set of circumstances has to exist, which includes freedom from genetic disease, absence of infectious agents, an optimal nutritional environment, and appropriate social forces. Should any of these factors be suboptimal, the attainment of full cognition will be denied. Certain factors such as exposure to infectious disease and inheritance of genetic abnormalities are beyond our control under most circumstances. However, if we fail to provide the optimal nutritional environment to achieve full competence intellectually because of our ignorance or failure to intercede, then this truly is a travesty.
underlying neurologic dysfunction does not. Another potential source of malnutrition impacting the nervous system would be the robust use of over-the-counter mineral supplements. In this context, for example, excessive supplementation with zinc is known to cause hypochromic anemia by inducing a functional copper deficiency. Excess nutrient intake itself can be toxic to brain development in addition to the imbalance suggested above. It is known, for example, that excess metal accumulation in the brain can be neurotoxic.1 Can a lack of a single nutrient during early development have a long-lasting affect on the nervous system? Recent research in the field of copper in rodent models indicates that this is indeed the case. By analogy to another essential trace metal, iron, it can be imagined that lack of essential copper during early development will have irreversible consequences to the central nervous system. The background information on brain and iron is discussed in another editorial in this issue of Nutrition.2
MALNUTRITION AND BRAIN DEVELOPMENT Malnutrition is a term that is often used to describe a number of circumstances in which the supply of adequate nutrients is less than adequate to support full biologic function. Perhaps the easiest scenario that can explain how malnutrition can have an impact on brain development is that in which the lack of an essential nutrient is involved. For example, the lack of one essential amino acid could limit the protein synthetic machinery and thus slow down biosynthesis and development. On a global scale, perhaps the most common nutrient deficit associated with an impairment in brain development is lack of sufficient energy to support the needs during gestational and lactational development. Another type of malnutrition that can have an impact on the nervous system and other biologic systems is when there is an imbalance of essential nutrients. We are all acquainted with the dangers in treating the anemia that accompanies vitamin-B12 deficiency with excess folate. The macrocytic anemia responds quite favorably, but the
Long-term financial support was provided by the USDA NRICGP for Copper Status and the Nervous System. Correspondence to: Joseph R. Prohaska, PhD, Department of Biochemistry and Molecular Biology, University of Minnesota, 252 School of Medicine, 10 University Drive, Duluth, MN 55812, USA. E-mail: jprohask@ d.umn.edu
NUTRITION AND BRAIN DEVELOPMENT Cellular events during brain development require a chemical milieu that ensures both differentiation and development occur in the right context, both spatially within the central nervous system and temporally. Early during development, the stem cells, which give rise to neurons, are rapidly dividing in a process referred to as hyperplasia. This process requires optimal nutrition. Later on, cells begin to differentiate and grow and mature in a process referred to as hypertrophy. Nutrition plays an important role. Nutrition also plays a role in ensuring that the correct number of cells is present after normal differentiation occurs. This process, conditioned apoptosis, is also influenced by a number of brain-derived growth factors. To have optimal development of the brain, there needs to be appropriate axonal outgrowth. Elaborations of these axons or growth cones require production of a number of trophic agents that are influenced by optimal nutrition. Once the axon arrives at its appropriate site within the nervous system, there is a necessary phenotypic maturation that occurs in which the development of synaptogenesis, the connection between two or more neurons, becomes very important. Optimal nutrition also plays a role in synaptogenesis. Related to synaptogenesis is another process referred to as plasticity or neuronal maturation and competition. Timing is critical for the proper development and specificity of these connections. Axonal and synaptic development is especially
Jansson and Powell
Nutrition Volume 16, Numbers 7/8, 2000
Placental Nutrient Transfer and Fetal Growth Thomas Jansson, MD, PhD, and Theresa L. Powell, PhD From the Perinatal Center, Department of Physiology and Pharmacology, Go¨teborg University, Go¨teborg, Sweden INTRODUCTION The placenta represents the interface between the mother and fetus and delivers all the nutrients necessary for normal fetal growth and development. Consequently, fetal growth is intimately linked to the transport functions of the placenta. Two important pregnancy complications are associated with altered fetal-growth patterns. In intrauterine growth restriction (IUGR), the fetus fails to achieve its genetically determined growth potential and is born with a low birth weight for gestational age. In contrast, some fetuses of mothers with diabetes represent the other end of the growth spectrum in displaying signs of fetal overgrowth. Historically, the restricted growth in IUGR has been attributed to reduced placental blood flow, and the accelerated fetal growth in some diabetic pregnancies has been explained by maternal hyperglycemia. However, a growing body of evidence is now available suggesting that alterations in the activity and expression of placental nutrient transporters may contribute to the development of these pregnancy complications. In the human placenta there are two cell layers positioned between the maternal and fetal blood circulations: the syncytiotrophoblast and the fetal capillary endothelium. For the primary fetal nutrients, such as glucose and amino acids, the plasma membranes of the syncytiotrophoblast cell constitutes the main barrier for transplacental transport. The syncytiotrophoblast is a true syncytium with polarized plasma membranes: the microvillous membrane (MVM) faces the maternal blood and the basal membrane (BM) is adjacent to the fetal capillary. As in other epithelial cells, differences in the type, number and activity of transporters in these two plasma membranes of the syncytiotrophoblast provide the basis for vectorial transport of nutrients. Thus, isolation of MVM and BM and the subsequent study of these membrane fractions in vitro is a valuable strategy to assess placental transport functions of the human placenta.
PLACENTAL NUTRIENT TRANSPORT IN IUGR IUGR remains an important obstetric and pediatric problem and is associated with increased perinatal morbidity, higher incidence of neurodevelopmental impairment,1 and increased risk for a number of diseases in adulthood such as cardiovascular disease and diabetes.2,3 Plasma concentrations of glucose4 and certain amino acids5 are decreased in the IUGR fetus in utero, findings that have provided the rationale for studying placental transport systems for these nutrients in IUGR. Of the approximately 15 different transporters for amino acids in the human placenta, the Na⫹-dependent system A transporter has attracted the most attention. IUGR is associated with a marked decrease in the activity of system A in MVM,6 – 8 whereas information about BM is less abundant.8 More
Supported by the Swedish Medical Research Council (10838 and 11834), Frimurare-Barnhus-direktionen, the Åhlens Foundation, Willhelm & Martina Lundgrens Foundation, Torsten and Ragnar So¨derbergs Foundation, and the Swedish Diabetes Association. Correspondence to: Thomas Jansson, MD, PhD, Perinatal Center, Department of Physiology and Pharmacology, Go¨teborg University, Box 432, S-405 30 Go¨teborg, Sweden. E-mail: [email protected]
recently, the activity of transporters for essential amino acids has been studied in isolated syncytiotrophoblast plasma membranes. In IUGR, leucine uptake was shown to be decreased in both MVM and BM, whereas the uptake of lysine was reduced in BM only.9 Furthermore, the activity of the taurine transporter is reduced in MVM in association with IUGR.10 Transplacental transport of glucose in the human is a facilitated process and mediated primarily by the glucose transporter isoform-1 (GLUT-1).11 Although fetal hypoglycemia is common in IUGR, placental GLUT-1 activity and protein expression were found to be unaltered in this pregnancy complication.11
PLACENTAL NUTRIENT TRANSPORT IN PREGNANCIES COMPLICATED BY MATERNAL DIABETES In pregnancies complicated by maternal diabetes, fetal overgrowth still constitutes a significant clinical problem. The birth of a large-for-gestational-age baby represents a potential complication by the increased incidence of operative delivery and birth trauma such as shoulder dystocia.12 It has been hypothesized that maternal hyperglycemia in diabetes increases placental glucose transfer, resulting in fetal hyperglycemia and increased fetal insulin concentrations, which in turn stimulates fetal growth.13 However, even in diabetic pregnancies with strict glycemic control, fetal overgrowth is not uncommon,14 suggesting a complex relationship between metabolic derangement and fetal growth in maternal diabetes.15 The possibility exists that the poor correlation between maternal glycemic control in diabetes and the incidence of fetal overgrowth observed in many studies is related to alterations in placental glucose-transport characteristics. Compatible with this hypothesis, we reported an increased placental glucose-transporter protein expression and glucose-transport activity in BM in a group of patients with insulin-dependent diabetes (IDDM) delivering large-for-gestational-age infants at term.16 In contrast, placental glucose transporters were unaffected in gestational diabetes (GDM), whereas the activity of system A amino acid transporter in MVM appears to be increased in GDM (Jansson, Ekstrand, Wennergren, and Powell, unpublished data). These latter findings are in contrast to a study by Kuruvilla et al. who reported a reduced system-A activity in MVM isolated from diabetic pregnancies associated with fetal overgrowth.17 The reasons for the discrepant results of the two studies are not immediately apparent.
ALTERATIONS OF PLACENTAL TRANSPORTERS—A MECHANISM FOR REGULATING FETAL GROWTH? Whereas, for example, growth hormone affects fetal growth to a rather limited extent, fetal insulin and insulinlike growth factors (IGFs) have a pronounced effect on the pattern of fetal growth. Insulin stimulates the growth of most fetal tissues, with the exception of the brain, which is relatively insulin insensitive. In most cases of IUGR, growth restriction is “asymmetric,” with growth of the brain relatively spared and the growth of, e.g., skeletal muscle and liver severely restricted. Therefore, the low plasma levels of fetal insulin, characteristic for IUGR, may represent an important signal for the impaired growth. Similarly, fetal overgrowth in
Nutrition Volume 16, Numbers 7/8, 2000 maternal diabetes during pregnancy may be the consequence of fetal hyperinsulinemia, as originally suggested by Pedersen.13 Insulin is secreted from the fetal endocrine pancreas in response to amino acids and glucose, providing a direct and efficient coupling between plasma concentrations of major nutrients and fetal growth. It has generally been believed that decreased substrate supply to the placenta (impaired placental blood flow or maternal malnutrition causing IUGR) and increased supply of major nutrients (hyperglycemia in maternal diabetes resulting in fetal overgrowth) directly alter the nutrient levels in the fetal circulation. This model, however, does not account for changes in placental transport functions. We propose that the placenta, rather than functioning as a mere conduit for maternofetal nutrient fluxes, adapts its transport functions in response to changes in substrate supply. As a consequence, alterations in the expression or activity of placental transporters may serve as a mechanism for regulating fetal growth. More specifically, we have suggested that the downregulation of placental amino-acid–transport systems may be one of the signals altering fetal growth patterns in the face of a compromised supply line in cases of IUGR.9,10 In addition, increased activity of system-A transporters in GDM (Jansson, Ekstrand, Wennergren, and Powell, unpublished data) and increased BM GLUT-1 protein expression and activity in IDDM16 may explain the occurrence of fetal overgrowth in maternal diabetes despite rigorous control of maternal blood-glucose levels. The evidence for an active role for the placenta in the adaptation of fetal growth to changes in nutrient supply are largely indirect. The specific upregulation of placental system A and glucose transporters in GDM and IDDM, respectively, indicate that the placenta has a capacity to respond to some nutritional stimuli with a change in selective transport systems. Furthermore, the alterations in placental transport systems in IUGR are specific in the sense that, whereas the activity of some amino-acid transporters is reduced, other transport systems remain unchanged. This suggests that these alterations are not a result of a general “toxic” or degenerative effect on the placenta of the IUGR fetus. The actual etiology for the IUGR in these human studies were unknown, but a reduced placental blood flow (“placental insufficiency”) was likely to be a main contributor to the restricted fetal growth in most cases. Maternal malnutrition is not a major cause for restricted fetal growth in the industrialized world, but it remains a severe problem in developing countries. Placental transport functions in malnutrition have not been studied in the human but have been addressed in experimental models. In the pregnant rat it was found that protein malnutrition caused IUGR and a decrease in the activity of placental system-A transporter and of y⫹L and y⫹ systems for cationic amino acids, whereas system B0,⫹ and alanine, serine, and cysteine (ASC) were unaffected.18 Despite the differences in species and the cause of IUGR, these changes mirror the alterations found in the human studies. Interestingly, despite the severe reduction in protein intake, maternal plasma concentrations of amino acids were largely unchanged, suggesting that the downregulation of placental transporters mediated the restricted fetal growth.18 These animal experimental studies provide more direct support to the idea that the placenta monitors or senses maternal nutritional status or nutrient supply to the placenta and alters its transport functions accordingly.
HOW DOES THE PLACENTA MONITOR CHANGES IN NUTRIENT SUPPLY? If the placenta has the ability to adapt its transport functions in response to nutrient supply, the underlying mechanisms remain to be defined. In particular, the nature of the “receptor” involved is speculative. For example, is the monitored parameter one of the major nutrients itself (amino acids, glucose) or possibly something related more directly to blood supply (e.g., tissue oxygenation)? One possibility to consider is that hormonal pathways are in-
Placental Nutrient Transfer and Fetal Growth
501
volved. The placenta is a tremendously versatile endocrine organ in producing almost all known hormones and growth factors. Among many potential candidates involved in regulation of placental transporters is placental growth hormone (pGH), which is produced by the syncytiotrophoblast and secreted into the maternal circulation.19 Glucose has been shown to regulate the release of pGH,20 and circulating levels of pGH are decreased in IUGR.21 Furthermore, the effects of pGH are mediated, at least in part, by the release of IGF-1 from the liver.19 IGF-1 has been shown to regulate the trophoblast system-A transporter.22 Thus, it is possible that changes in nutrient supply to the placenta affect the activity of the placental system-A transporter mediated by pGH and IGF-1.
FUTURE DIRECTIONS FOR RESEARCH The study of placental nutrient transport is still in its infancy. Much of the research thus far has been descriptive in providing some of the information necessary to define the cellular mechanisms for transplacental transport. The findings that the activity and expression of placental transporters are altered in pregnancy complications clearly suggest that these transporters are subjected to regulation in vivo, and this will stimulate detailed studies of transporter regulation in the near future. A particularly challenging area will be to unravel the complex interactions between maternal nutrition, placental function, and fetal growth. This work will require an integrative approach employing a wide range of methods, from molecular biology to whole-animal physiology and experimental systems, such as isolated membranes, cells, and fragments, perfused cotyledons, and animal models representing several different species. Studies in pregnant women using recently developed stable isotope techniques will be valuable in the efforts to obtain a better understanding of the metabolism and transport of nutrients in vivo. The development of transgenic mice with genes encoding for nutrient transporters over- and underexpressed in the trophoblast would represent an important tool in future research in this area.
REFERENCES 1. Blair E, Stanley F. Intrauterine growth and spastic cerebral palsy. I. Association with birth weight for gestational age. Am J Obstet Gynecol 1990;162:229 2. Hales CN, Barker DJP, Clark PMS, et al. Fetal and infant growth and impaired glucose tolerance at age 64. Br Med J 1991;303:1019 3. Barker DJP, Gluckman PD, Godfrey KM, et al. Fetal nutrition and cardiovascular disease in adult life. Lancet 1993;341:938 4. Economides DL, Nicolaides KH. Blood glucose and oxygen tension in smallfor-gestational-age fetuses. Am J Obstet Gynecol 1989;160:120 5. Cetin I, Marconi AM, Bozzetti P, et al. Umbilical amino acid concentrations in appropriate and small for gestational age infants: a biochemical difference present in utero. Am J Obstet Gynecol 1988;158:120 6. Mahendran D, Donnai P, Glazier JD, et al. Amino acid (system A) transporter activity in microvillous membrane vesicles from the placentas of appropriate and small for gestational age babies. Pediatr Res 1993;34:661 7. Dicke JM, Henderson GI. Placental amino acid uptake in normal and complicated pregnancies. Am J Med Sci 1988;295:223 8. Dicke JM, Verges DK. Neutral amino acid uptake by microvillous and basal plasma membrane vesicles from appropriate- and small-for-gestational age human pregnancies. J Mater Fetal Med 1994;3:246 9. Jansson T, Scholtbach V, Powell TL. Placental transport of leucine and lysine is reduced in intrauterine growth restriction. Pediatr Res 1998;44:532 10. Norberg S, Powell TL, Jansson T. Intrauterine growth restriction is associated with a reduced activity of placental taurine transporters. Pediatr Res 1998;44:233 11. Jansson T, Wennergren M, Illsley NP. Glucose transporter protein expression in human placenta throughout gestation and in intrauterine growth retardation. J Clin Endocrinol Metab 1993;77:1554 12. Casey BM, Lucas MJ, McIntire DD, Leveno KJ. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90:869 13. Pedersen J. Weight and length at birth of infants of diabetic mothers. Acta Endocrinol 1954;16:330
502
Prohaska
14. Garner P. Type I diabetes mellitus and pregnancy. Lancet 1995;346:157 15. Freinkel N. Of pregnancy and progeny. Diabetes 1980;29:1023–35 16. Jansson T, Wennergren M, Powell TL. Placental glucose transport and GLUT 1 expression in insulin dependent diabetes. Am J Obstet Gynecol 1999;180:163 17. Kuruvilla AG, D’Souza SW, Glazier JD, et al. Altered activity of the system A amino acid transporter in microvillous membrane vesicles from placentas of macrosomic babies born to diabetic women. J Clin Invest 1994;94:689 18. Malandro MS, Beveridge MJ, Kihlberg MS, Novak DA. Effect of low-protein diet-induced intrauterine growth retardation on rat placental amino acid transport. Am J Physiol 1996;271:C295
Nutrition Volume 16, Numbers 7/8, 2000 19. Alsat E, Guibourdenche J, Luton D, Frankenne F, Evain-Brion D. Human placental growth hormone. Am J Obstet Gynecol 1997;177:1526 20. Patel N, Alsat E, Igout A, et al. Glucose inhibits human placental GH secretion, in vitro. J Clin Endocrinol Metab 1995;80:1743 21. Mirlesse V, Frankenne F, Alsat E, et al. Placental growth hormone levels in pregnancies with intrauterine growth retardation. Pediatr Res 1993;34:439 22. Bloxam DL, Bax BE, Bax CMR. Epidermal growth factor and insulin-like growth factor I differentially influence the directional accumulation and transfer of 2-aminoisobutyrate (AIB) by human placental trophoblast in two-sided culture. Biochim Biophys Res Commun 1994;199:922
Long-Term Functional Consequences of Malnutrition During Brain Development: Copper Joseph R. Prohaska, PhD From the Department of Biochemistry and Molecular Biology, School of Medicine, University of Minnesota, Duluth, Minnesota, USA INTRODUCTION As we begin a new century, it seems clear that the future of our world will be dependent on the cognition and judgment shown by new leaders in making the most of the resources that exist on our planet. To develop that full cognition, a desirable set of circumstances has to exist, which includes freedom from genetic disease, absence of infectious agents, an optimal nutritional environment, and appropriate social forces. Should any of these factors be suboptimal, the attainment of full cognition will be denied. Certain factors such as exposure to infectious disease and inheritance of genetic abnormalities are beyond our control under most circumstances. However, if we fail to provide the optimal nutritional environment to achieve full competence intellectually because of our ignorance or failure to intercede, then this truly is a travesty.
underlying neurologic dysfunction does not. Another potential source of malnutrition impacting the nervous system would be the robust use of over-the-counter mineral supplements. In this context, for example, excessive supplementation with zinc is known to cause hypochromic anemia by inducing a functional copper deficiency. Excess nutrient intake itself can be toxic to brain development in addition to the imbalance suggested above. It is known, for example, that excess metal accumulation in the brain can be neurotoxic.1 Can a lack of a single nutrient during early development have a long-lasting affect on the nervous system? Recent research in the field of copper in rodent models indicates that this is indeed the case. By analogy to another essential trace metal, iron, it can be imagined that lack of essential copper during early development will have irreversible consequences to the central nervous system. The background information on brain and iron is discussed in another editorial in this issue of Nutrition.2
MALNUTRITION AND BRAIN DEVELOPMENT Malnutrition is a term that is often used to describe a number of circumstances in which the supply of adequate nutrients is less than adequate to support full biologic function. Perhaps the easiest scenario that can explain how malnutrition can have an impact on brain development is that in which the lack of an essential nutrient is involved. For example, the lack of one essential amino acid could limit the protein synthetic machinery and thus slow down biosynthesis and development. On a global scale, perhaps the most common nutrient deficit associated with an impairment in brain development is lack of sufficient energy to support the needs during gestational and lactational development. Another type of malnutrition that can have an impact on the nervous system and other biologic systems is when there is an imbalance of essential nutrients. We are all acquainted with the dangers in treating the anemia that accompanies vitamin-B12 deficiency with excess folate. The macrocytic anemia responds quite favorably, but the
Long-term financial support was provided by the USDA NRICGP for Copper Status and the Nervous System. Correspondence to: Joseph R. Prohaska, PhD, Department of Biochemistry and Molecular Biology, University of Minnesota, 252 School of Medicine, 10 University Drive, Duluth, MN 55812, USA. E-mail: jprohask@ d.umn.edu
NUTRITION AND BRAIN DEVELOPMENT Cellular events during brain development require a chemical milieu that ensures both differentiation and development occur in the right context, both spatially within the central nervous system and temporally. Early during development, the stem cells, which give rise to neurons, are rapidly dividing in a process referred to as hyperplasia. This process requires optimal nutrition. Later on, cells begin to differentiate and grow and mature in a process referred to as hypertrophy. Nutrition plays an important role. Nutrition also plays a role in ensuring that the correct number of cells is present after normal differentiation occurs. This process, conditioned apoptosis, is also influenced by a number of brain-derived growth factors. To have optimal development of the brain, there needs to be appropriate axonal outgrowth. Elaborations of these axons or growth cones require production of a number of trophic agents that are influenced by optimal nutrition. Once the axon arrives at its appropriate site within the nervous system, there is a necessary phenotypic maturation that occurs in which the development of synaptogenesis, the connection between two or more neurons, becomes very important. Optimal nutrition also plays a role in synaptogenesis. Related to synaptogenesis is another process referred to as plasticity or neuronal maturation and competition. Timing is critical for the proper development and specificity of these connections. Axonal and synaptic development is especially