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Low Serine Hydroxymethyltransferase Activity in the Human Placenta Has Important Implications for Fetal Glycine Supply

Centre for the Developmental Origins of Health and Disease (R.M.L., I.T.C., M.A.H.), University of Southampton, Princess Anne Hospital, SO16 5YA Southampton, United Kingdom; Medical Research Council Epidemiology Resource Centre (K.M.G.), University of Southampton, SO16 6YD Southampton, United Kingdom; and Institute of Human Nutrition (A.A.J.), University of Southampton, Southampton General Hospital, SO16 6YD Southampton, United Kingdom

Address all correspondence and requests for reprints to: Dr. Rohan Lewis, Centre for the Developmental Origins of Health and Disease, University of Southampton, Princess Anne Hospital, SO16 5YA Southampton, United Kingdom. E-mail: rml2{at}soton.ac.uk.

	Abstract

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Glycine is essential for fetal development, but in both sheep and human pregnancy, little is transported directly from the mother to the fetus, indicating that fetal glycine is derived from other sources. In the sheep, placental conversion of maternal serine by serine hydroxymethyltransferase (SHMT) provides almost all the glycine transported to the fetus. Although mRNA for mitochondrial and cytoplasmic SHMT has been detected in human placenta, it is not known whether substantial placental conversion of serine to glycine occurs in species other than sheep. We determined SHMT activity in human, rat, and sheep placenta by measuring conversion of [3-¹⁴C]serine to ¹⁴C-methylene tetrahydrofolate. Compared with term human placenta, SHMT activity per gram of placenta was 5.1-fold higher in term rat placenta and 24.1-fold higher in term sheep placenta. In sheep placenta, SHMT activity per gram of placenta increased 2.1-fold between mid-gestation and term. In human placenta, placental SHMT activity was similar 8 wk post conception and at term. The low activity of SHMT in the human and rat placenta suggests that, unlike in the sheep, placental conversion of serine to glycine is not a major source of fetal glycine in these species.

	Introduction

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THE FETUS REQUIRES large amounts of glycine to meet both structural and metabolic demands. However, glycine is not transported to the human fetus at a high rate, and evidence from preterm babies suggests that the fetus cannot synthesize enough glycine to meet its requirements (1, 2, 3). Therefore, it has been proposed that, during fetal life, glycine is a conditionally essential amino acid (2). For this reason, it is important to understand how glycine is delivered to the human fetus.

Glycine is the simplest amino acid, with no side chain. As a result, glycine is of particular importance as a structural unit in proteins, such as collagens, and in many metabolic pathways as a source of one-carbon units. In mammals, collagen contains over 30% glycine, and collagens make up 20–25% of the body’s protein (4). Glycine is also essential as a metabolic precursor. Many of the products of glycine metabolism, such as the nucleic acids, heme, and creatine, represent the end point of its metabolism, in that they cannot be recycled to glycine, and the glycine used for these pathways is lost from the glycine pool. Thus, the fetus requires disproportionately large amounts of glycine both for structural development and as a metabolic precursor.

Maternal-fetal enrichment of glycine in the human fetus is much lower than for the essential amino acids leucine and phenylalanine, suggesting that maternal glycine transport is unlikely to meet high fetal glycine requirements (1, 3). After the administration of ¹⁵N glycine to preterm infants, there is almost no appearance of ¹⁵N urea in the urine. This suggests that the demand for glycine exceeds the available supply and indicates that the preterm infant is not able to produce enough glycine by de novo synthesis to meet its requirements (2). Glycine’s importance to the fetus is illustrated by studies in which feeding rats a low-protein diet during pregnancy caused impaired vascular function and elevated blood pressure in the adult offspring (5, 6, 7). Supplementing the maternal low-protein diet with glycine, but not alanine, prevented the development of elevated blood pressure and vascular dysfunction in the offspring (6, 8). Thus, the role of the maternoplacental unit in delivering glycine to the fetus is crucial not just during fetal life but throughout the lifespan. These observations have important implications for human pregnancy because a high proportion of pregnant women exhibit markers of glycine insufficiency, reflected in increased conversion of glutamylcysteine to 5-L-oxoproline; even in normal pregnant women, 5-L-oxoproline excretion rates increase 3–10 times over nonpregnant values (9).

Serine hydroxymethyltransferase (SHMT) (10) plays a central role in serine and glycine transport to the sheep fetus (Fig. 1). The sheep placenta does not transport maternal serine directly to the fetus. Instead, placental SHMT converts maternal serine to glycine, and this glycine is transported to the fetus. Some of this glycine is then reconverted to serine within the fetus to meet fetal serine demands. Fetal serine is also taken up by the placenta, where it is converted to glycine and reexported to the fetus, resulting in cycling of serine and glycine between the placenta and the fetal liver (10).

View larger version (26K): [in this window] [in a new window]   FIG. 1. Serine and glycine transport and metabolism by SHMT in the epitheliochorial sheep placenta based on Geddie et al. (10 ).

Because glycine is essential to the fetus and appears to be poorly transported across the placenta, it has been hypothesized that placental conversion of serine to glycine is an important source of fetal glycine in human pregnancy, as in the sheep. This hypothesis is supported by umbilical arterial-venous difference data indicating that, as in the sheep, there is net placental serine uptake (13). If this hypothesis is correct, SHMT activity would be expected to be present at high levels in the human placenta. To address this question, we measured the levels of SHMT activity in human, rat, and sheep placenta; in human and sheep placental samples, we also measured SHMT activity in both early and late gestation. To examine the relationship between placental SHMT activity and fetal growth, we related activity in the term human placenta to infant weight at birth.

	Materials and Methods

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Tissue collection

All procedures involving animals were conducted in accordance with the United Kingdom Animals (Scientific Procedures) Act of 1996. Human tissues were collected after informed written consent and with the approval of the Southampton and South West Hampshire Local Research Ethics Committees.

Placenta was collected from six pregnant Wistar rat dams on d 21 of gestation (term is d 22). The dams were fed ad libitum a nutritionally complete diet (K4447.01; Hope Farms, Waerden, The Netherlands) containing 17.5% crude protein, 5.2% fat, and 66.2% sugar and starch, with a gross energy content of 15.7 MJ/kg. The placentas from each litter were pooled, snap frozen, and stored at –80 C. Pooled rat placentas were powdered so that the tissue sampled in the assay was representative of the litter as a whole.

Sheep placental cotyledons were collected from Welsh Mountain Ewes in separate studies at d 70 of gestation (n = 6) and at term in the last week of pregnancy (n = 6). In the term study, labor was induced using a fetal infusion of dexamethasone (1 mg/d) on d 139 (term is around d 146), and type C or D cotyledons were collected after caesarean section on d 141. Animals were considered to be in labor when uterine contractions, as recorded by uterine electromyograph, reached twice baseline. Diet in the midterm group was a pelleted diet consisting of barley, wheat, cooked cereal meal, micronized full-fat soya, grass meal, molasses, chopped straw, calcium carbonate, dicalcium phosphate, salt, and a sheep vitamin/mineral supplement (14). Diet in the term study was based on a mixture of maize silage, grass silage, and concentrates with added SoyPreme (Borregaard UK Ltd., Warrington, UK) (170–200 g/d). The amount of diet fed was calculated individually to meet the maintenance requirements of each ewe according to weight and stage of gestation. Cotyledons were frozen and stored at –80 C. Again, frozen cotyledons were powdered so that the tissue sampled was representative of the cotyledon as a whole.

Human term placental tissue was collected within 30 min of delivery and snap frozen in liquid nitrogen. First trimester human placental tissue was collected from six women who underwent elective termination of pregnancy at 8–9 wk post conception (10–11 wk gestation from last menstrual period); the tissue was frozen on dry ice and stored at –80 C.

SHMT assay

SHMT activity was measured using a method based on that of Geller and Kotb (11), which measures the conversion of L-[3-¹⁴C]serine (Amersham Pharmacia Biotech, Bucks, UK) to ¹⁴C-methylene tetrahydrofolate. Tissue was homogenized using a mechanical homogenizer to 0.2 g/ml in ice-cold 0.25 M sucrose and 10 mM Tris HCl (pH 8) to which broad spectrum protease inhibitor tablets had been added (Roche, Mannheim, Germany). The tissue homogenate was then spun at 4000 rpm for 5 min to remove debris and stored at –80 C. SHMT activity remained consistent over at least 4 months when stored at –80 C.

The assay buffer contained 50 mM Tris HCl buffer (pH 8), containing 2 mM 5,6,7,8-tetrahydropteroyl-L-glutamic acid (Sigma, Dorset, UK), 0.25 mM pyridoxal 5'phosphate (Acros Organics, Loughborough, Leicestershire, UK), 5 mM EDTA, 3 mM dithiothreitol, 0.3 mM serine, and about 100,000 cpm/100 µl reaction L-[3-¹⁴C]serine. Reactions were started by mixing tissue homogenate and the reaction buffer to give a total volume of 100 µl and carried out at 37 C. For consistency, this temperature was used for all species. For our experiments, aliquots of 25 µl were removed at 11 min and spotted onto DE-81 cellulose paper (Whatman, Maidstone, England). This time point was chosen because it was the shortest time point that allowed all the species and gestational ages to be compared in the same assay. However, the groups (rat, sheep, and human) were also compared individually, which allowed sampling of 25-µl aliquots at two time points (7.5 and 15 min), enabling us to ensure that the results were consistent at the two time points. Once the spots had dried, the paper was washed with 5 x 2 liter deionized water over 20 min to remove L-[3-¹⁴C]serine. The paper was then dried, and the counts in each square were determined by liquid scintillation counting. Activity increased in a linear manner with time and concentration (Fig. 2). Because the serine to glycine conversion mediated by SHMT is reversible, adding excess glycine to the reaction should drive the reaction backwards. The specificity of the assay was demonstrated by showing that glycine added at 5 min reversed the reaction and resulted in lower levels of ¹⁴C-methylene tetrahydrofolate binding to the DE-81 cellulose paper at 10 min than at 5 min (data not shown). Data were expressed as nanomole of ¹⁴C-methylene tetrahydrofolate production per milligram of placental protein^–1 per second–¹ (nmol/mg^–1·sec^–1), as micromole of ¹⁴C-methylene tetrahydrofolate production per gram of placental tissue^–1 per second^–1 (µmol/g_placenta^–1·sec^–1), and as nanomole of ¹⁴C-methylene tetrahydrofolate per gram of fetal weight in term placentas^–1 per second^–1 (µmol/g_fetus^–1·sec^–1). The interassay coefficient of variation of the SHMT assay was 15%.

View larger version (17K): [in this window] [in a new window]   FIG. 2. SHMT activity in a sample of sheep placental homogenate demonstrating that activity increases in a linear manner over a range of concentrations and incubation times.

Statistical analysis

Statistical analysis was performed using SPSS 11.5 for Windows (SPSS, Chicago, IL). Differences between the groups were analyzed by ANOVA followed by Dunnett’s T3 post hoc test, which takes into account that the variances were not equal between the groups. Correlations were performed using the Spearman test.

	Results

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SHMT activity was detected in human, rat, and sheep placenta. The levels of SHMT activity were, however, considerably higher in sheep placenta than in rat or human placenta. Compared with term human placenta, SHMT activity in d 141 sheep placenta was 33-fold higher per milligram of placental protein (P < 0.001; Fig. 3) and 24-fold higher per gram of placental tissue (P < 0.001; Fig. 4). SHMT activity per milligram of placental protein in d 21 rat placenta was 4.7-fold higher than in the human term placenta (P < 0.001) but 6.9-fold lower than in the d 141 sheep placenta (P < 0.001; Fig. 3). Per gram of placental tissue, rat placental SHMT activity was 7-fold higher than in term human placenta (P < 0.001; Fig. 4) and 5-fold lower than in d 141 sheep placenta (P < 0.001; Fig. 4).

View larger version (16K): [in this window] [in a new window]   FIG. 3. Placental SHMT activity per milligram of placental protein (nmol/mg placental protein·sec–1). Data are expressed as mean ± 95% confidence intervals (n = 6 in each group). Significance is indicated where the letters above the columns are different (P < 0.005).

View larger version (17K): [in this window] [in a new window]   FIG. 4. Placental SHMT activity per gram of placental tissue (µmol/gplacenta–1·sec–1). Data are expressed as mean ± 95% confidence intervals (n = 6 in each group). Significance is indicated where the letters above the columns are different (P < 0.005).

In the human placental samples, SHMT activity 8 wk post conception (10–11 wk after last menstrual period) tended to be higher than at term, but this was not statistically significant (Figs. 3 and 4). SHMT activity per milligram of placental protein was not significantly different between the d 70 and d 141 sheep placenta (Fig. 3), but when expressed per gram of placental tissue, SHMT activity in the sheep placenta was 2.1-fold higher at term than at d 70 (P < 0.002; Fig. 4).

To determine how placental SHMT activity compared between species given the differences in relative fetal and placental weights at term, we calculated placental SHMT activity per gram of fetal tissue. Compared with human pregnancy, placental SHMT activity per gram of fetal tissue at term was 3.9-fold higher in the rat placenta and 9.4-fold higher in the sheep placenta (P < 0.001; Fig. 5). Placental SHMT activity per gram of fetal tissue was 2.4-fold higher in the sheep than in the rat (P < 0.05; Fig. 5).

View larger version (15K): [in this window] [in a new window]   FIG. 5. Placental SHMT activity per gram of fetal weight in term placentas (nmol/gfetus–1·sec–1). Data are expressed as mean ± 95% confidence intervals (n = 6 in each group). Significance is indicated where the letters above the columns are different (P < 0.05).

	Discussion

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Whether expressed per milligram of placental protein, per gram of placenta, or taking into account the differences in fetoplacental ratio between species, we found that placental SHMT activity differed greatly between species and was considerably lower in humans and rats than in sheep. The temperature at which we performed our assays (37 C) was slightly lower than ovine body temperature (39 C); if anything, this would tend to underestimate activity in the sheep and cannot account for the difference we observed. Our findings make it unlikely that conversion of serine to glycine is occurring at high rates in the human or rat placenta and suggests that, in these species, SHMT does not play a central role in maternofetal glycine transport as it does in the sheep. The only other species in which placental SHMT levels have been measured is the rabbit, where levels were also low (15), suggesting that high placental SHMT levels may have a restricted species distribution.

In the context of previous studies showing high fetal glycine demand and relatively low rates of maternofetal enrichment of glycine across the human placenta (1, 3), our finding of a low level of placental SHMT, indicating low serine to glycine conversion in the placenta, raises the major question of how the human fetus obtains the large quantities of glycine that it requires for normal development.

Although glycine can be synthesized from a variety of substrates, the major physiological source in mammals is serine via the action of SHMT (4). As such, there are three primary sources of glycine for the fetus, which are transplacental glycine transport, transplacental serine transport, and fetal glycine or serine synthesis. Glycine is transported across the human placenta, but it has a relatively low fetomaternal enrichment compared with other amino acids (1, 3), and it is questionable whether the rate of transport would be sufficient to meet fetal glycine demand. Based on an umbilical arterial-venous difference for glycine of approximately 10 µmol/liter (13) and an umbilical blood flow near term of 0.108 liter/kg/min (16), placental glycine transport for a 3.2-kg fetus is around 370 mg/d. Widdowson et al. (17) reported that fetal glycine accretion between d 260 and 280 of gestation is 476 mg/d, suggesting that placental glycine supply to the fetus may be about 30% below fetal requirements before taking into account the glycine required for biosynthesis or energy metabolism. Serine transport across the placenta has not been well characterized in human pregnancy. Studies of umbilical arterial-venous differences suggest either little net serine transport across the placenta or placental uptake of serine (13, 18). If this is correct, then maternal serine will not be a significant source of fetal glycine. However, there is evidence that serine does cross the placenta from studies of maternal amino acid supplementation in which higher levels of maternal serine corresponded to higher serine levels in the umbilical vein (19). Before maternal serine is ruled out as a significant source of fetal glycine, we need direct measurements of maternal-fetal serine transport and fetal-placental serine uptake. Another possibility is that the fetus synthesizes glycine and serine from other sources, such as from glucose via 3-phosphoglycerate. This pathway is potentially a major source of glycine, but the extent to which the fetus is capable of synthesizing glycine is unclear, and studies in premature infants suggest that it may be very limited (2). We suggest that fetal serine synthesis is likely to be a major source of both fetal serine and glycine (Fig. 6).

View larger version (23K): [in this window] [in a new window]   FIG. 6. Serine and glycine transport across the human placenta. The fetus may obtain glycine from three sources, which include transplacental glycine transport, transplacental serine transport, and conversion of maternal serine to glycine by fetal SHMT. 3PG, 3-Phosphoglycerate.

The net fetal-placental uptake of serine has been taken to suggest that fetal-placental cycling of serine and glycine, which is mediated by placental SHMT, also occurs in the human (13). However, this would seem unlikely given the results of this study. We cannot exclude the possibility that in vivo SHMT activity is higher in the human placenta than is suggested by our in vitro assay. As such, an in vivo or ex vivo determination of placental serine to glycine conversion would be useful to settle this issue.

The differences in SHMT activity, and potentially serine and glycine transport and metabolism, between species may originate from differences in placenta structure. The sheep placenta is epitheliochorial, having both maternal and fetal compartments separating the maternal and fetal blood, and it may be this two-compartment structure that prevents the direct transfer of maternal serine to the fetus. There is some evidence that there are two distinct serine pools in the ovine placenta, indicating that serine may not easily cross the barrier between the fetomaternal syncytial layer and the fetal epithelial layer (10). If this is the case, then the system in the sheep may have evolved to facilitate serine transport to the fetus.

Because there was no difference in SHMT activity between natural deliveries and caesarean sections and no difference in sheep SHMT activity per milligram of placental protein between midterm and labor, we do not think that labor affects SHMT activity. However, it remains a possibility that the rat data, which were determined in placentas collected the day before birth, are not directly comparable to the human and sheep data.

Sheep placental SHMT activity has previously been reported to be similar throughout gestation when expressed per milligram of cytoplasmic or mitochondrial protein (10), which is consistent with our findings per milligram of placental protein. However, when placental SHMT activity is expressed per gram of placental tissue, SHMT activity is 2.1-fold higher on d 141 of gestation when compared with the activity on d 70 of gestation. This is due to an increase in placental protein per gram of tissue between d 70 and d 141. This corresponds to a large increase in the placental capacity to convert serine to glycine and may occur in response to growing fetal demand for nutrients.

In conclusion, our studies demonstrate the need for further cross-species studies of placental amino acid transport; although this is well characterized in the sheep, and there are similarities for some amino acids such as leucine (20, 21), our data suggest that there are significant differences in placental serine and glycine transport between the human and the sheep. The present study focuses attention on how human and rat fetuses obtain glycine, if there is little placental production of glycine by SHMT. We hypothesize that fetal conversion of serine, derived from fetal metabolism, may contribute significantly to the fetal glycine pool in human and rat pregnancy.

	Acknowledgments

 
We thank the staff at the Princess Anne Hospital for their assistance in the collection of placental tissue and the staff at the Centre for the Developmental Origins of Health and Disease for their help in the collection of sheep placenta.

	Footnotes

 
First Published Online December 14, 2004

Abbreviation: SHMT, Serine hydroxymethyltransferase.

Received February 18, 2004.

Accepted December 2, 2004.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lewis, R. M. Articles by Hanson, M. A. Search for Related Content PubMed PubMed Citation Articles by Lewis, R. M. Articles by Hanson, M. A. Related Collections Pediatric Endocrinology Female Endocrinology