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The Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, Scotland, UK
3 To whom correspondence should be addressed. E-mail: wdr{at}rri.sari.ac.uk.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • methionine • pregnancy • maternal diet
The developing fetus is dependent on its mother for a supply of nutrients to support the high rates of cell division that are found during the early stages of life. Methionine is one of these indispensable nutrients, required for protein synthesis and the production of S-adenosyl methionine (SAM),4 which is essential for the biosynthesis of key components such as phospholipids. The methionine supply can also influence wider aspects of gene expression because SAM is essential for the regulation of chromatin function. However, excess methionine in the maternal diet is also detrimental to fetal development. Suboptimal growth in utero has a long-lasting influence on the offspring because of the large number of cell divisions that take place during this period. It has been estimated that an individual cell undergoes 47 cell divisions, from the fertilized oocyte to an adult tissue; however, only 5 of these cell divisions take place after birth (1). Because poor development increases the risk of disease in postnatal life (2), improving fetal nutrition through the provision of an optimal balance of amino acids in the maternal diet is an important long-term goal.
Methionine and protein turnover during pregnancy. During pregnancy there is net gain of protein by both the mother and the fetus, increasing the demand for amino acids including methionine. These amino acids are derived from the turnover of maternal proteins as well as from the diet. In humans the mother's body composition and the rate of visceral protein turnover have an important influence on the fetal amino acid supply (3). Because the balance of amino acids produced by the breakdown of maternal proteins is probably similar to that of the proteins synthesized by the fetus, there is unlikely to be a need for the large-scale catabolism of amino acids that cannot be utilized. In contrast, dietary proteins may yield an unbalanced mixture that restricts protein synthesis because of the reduced availability of the limiting amino acid. Any excess amino acids derived from the diet have to be diverted into catabolic pathways. As discussed below, both glycine and serine are required for the catabolism of excess dietary methionine, so an imbalance in the diet may lead to an unexpected deficiency. There is evidence to suggest that quite small increases in methionine intake can reduce the glycine supply during gestation. Methionine supplementation of the maternal diet to improve fetal growth through enhanced protein synthesis should therefore be approached with caution because any imbalance may worsen rather than improve the supply of particular amino acids.
The metabolism of methionine during pregnancy. During pregnancy, methionine continues to be metabolized by a series of metabolic pathways that have the nonprotein amino acid homocysteine as a central component (Fig. 1). By acquiring a methyl group from either methylated folates or from betaine (derived from choline), homocysteine is converted back to methionine, completing the cycle. The flux through the remethylation reactions increases when methionine is limited and is dependent on the availability of choline, betaine, and folic acid in the diet (4). The size of the homocysteine pool is determined by the rate of its production, the rate of reconversion to methionine, and also the rate of transsulfuration of homocysteine to produce cysteine and taurine. Changes in plasma homocysteine are believed to reflect the activity of the methionine cycle.
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The production of S-adenosyl methionine. S-Adenosyl methionine (SAM) is an essential substrate for transmethylation reactions in which the methyl group is donated to a range of acceptor substrates including phospholipids, DNA, and proteins. Two isoforms of the essential enzyme methionine adenosyltransferase catalyze the biosynthesis of SAM from methionine. The regulation of this enzyme is complex and dependent on endocrine and nutritional factors (7). Changes in the activity and regulation of these components have not been studied in pregnancy; however, in the adult liver this enzyme is an important regulator of hepatic function and is one of the activities that is increased when animals adapt to excess methionine in the diet (8). These regulatory functions appear to maintain circulating methionine and intracellular SAM concentrations within quite narrow limits.
SAM as a substrate for the methylation of DNA and proteins. The close control of SAM concentrations may be required because it is an essential substrate for the covalent methylation of DNA and proteins. These methylation reactions regulate gene expression during development and depend on SAM because the enzymes involved cannot utilize other methyl donors (9,10). It is conceivable that increases in the intracellular concentrations of SAM above the normal concentrations could cause a substrate-mediated increase in the activity of the methyltransferase enzymes and cause hypermethylation of the substrate. This in turn may interfere with the process of chromatin remodeling and cause changes in the subsequent expression of genes.
The changes in DNA and chromatin structure (often referred to as epigenetic programming) are particularly important during preimplantation development when major rearrangements of chromatin take place. Animals with knockout phenotypes lacking the key DNA methyl transferases (11) or histone methyl transferases (12) are infertile because development fails in these early stages. The preimplantation embryo is dependent on the surrounding medium for its supply of amino acids. The uterine fluid is derived from the circulation, so the embryo derives some protection from the adverse effects of excess dietary methionine by the metabolic processes that maintain circulating concentrations. When there is a severe imbalance in the diet (for example, a 6% casein diet containing 5% methionine), endocrine mechanisms involving estrogen and progesterone appear to block reproduction (13). However, these protective mechanisms are not present when embryos are cultured in vitro. An inappropriate balance of methionine and other amino acids in the culture medium has the potential to alter methionine metabolism and the all-important intracellular SAM concentrations. Embryo culture techniques in farm animals have been shown to cause defective epigenetic programming, changes in the expression of key genes, and a number of developmental abnormalities collectively known as the large-offspring syndrome (14,15). Recent observations also suggest a link between assisted reproductive technology and epigenetic errors in humans. In this context, avoiding an excess of methionine and providing sufficient glycine in the medium may be very important in minimizing the impact of embryo culture (16).
SAM as a substrate for biosynthesis during development. As the fetus develops, there is also a change in the biosynthetic reactions that use SAM. These include the synthesis of phosphatidyl choline (PC), which is a critical component of cell membranes and in particular the developing neural tissue (17). When choline provided by the diet cannot support the demand for PC, the enzyme phosphatidyl ethanolamine methyl transferase (PEMT) converts phosphatidyl ethanolamine to PC using methyl groups derived from 3 molecules of SAM. Studies of animals with a genetic defects in PEMT show that phospholipid methylation in the liver is a major consumer of SAM (18). In rats there is a depletion of choline pools during pregnancy (19), suggesting that the choline requirement is significantly increased during gestation. The impact of these changing requirements on the flux through the SAM pool is unclear. It is likely that the activity of the enzymes involved will gradually change to adapt to both the changing requirements of the fetus and the availability of the products in the diet. The precise impacts of sudden changes in diet composition caused by the use of supplements are unknown. Sudden changes in the composition of the diet may lead to a transient loss of control until the corresponding enzyme activities are up-regulated by changes in gene expression. Equally, the removal of an essential product such as choline from the diet can create a sudden demand for methyl groups to support biosynthesis. The impact of large-scale manipulation of the maternal diet remains to be investigated.
Homocysteine and pregnancy. When methionine is in excess, there is an increase in the flux through the homocysteine pool and an increase in the plasma concentration. In humans, elevated plasma homocysteine concentrations are associated with common pregnancy complications and adverse outcomes, including preeclampsia, spontaneous abortion, placental abruption, and recurrent pregnancy loss (20). Extreme elevation of homocysteine may also be associated with neural tube defects (21). Administering homocysteine to developing chick embryos causes defects in the extraembryonic vasculature (22), neural development (23), and neural crest morphogenesis (24). The precise mechanisms of homocysteine toxicity are unclear and vary among different cell types. Homocysteine toxicity may be mediated directly by S-adenosyl homocysteine (SAHcy) interfering with the process of DNA and histone methylation. Experiments in vitro have shown that SAHcy is a competitive product inhibitor of DNA methyl transferase (25) and of histone methyl transferase (26); however, at present there is no evidence for an effect of elevated intracellular SAHcy concentrations on the epigenetic regulation of gene expression in vivo. Other proposed mechanisms for the toxic effects of homocysteine are direct or indirect perturbation of redox homeostasis, binding to nitric oxide, and the production of homocysteinylated/acylated proteins. It is not known whether elevated maternal homocysteine causes a corresponding increase in the fetus or whether it interferes with fetal development through some or all of these mechanisms.
The long-term consequences of perturbed methionine metabolism: rodent studies. Because of their short life span, laboratory rodents have been widely used to investigate the long-term impact of maternal nutrition on fetal development and postnatal health (27). The pregnant rat fed a low-protein diet is widely used as an experimental model with the offspring demonstrating changes in cardiovascular and metabolic functions in adult life (28). In this paradigm, animals are fed diets containing 8 to 9% casein and are compared with control animals fed a high-protein diet containing 18 to 22% casein (29,30). Although casein is a highly digestible protein, it has a relatively low content of cysteine and fails to meet the sulfur amino acid requirements of the growing rat. This deficiency is corrected by supplementing the diet with additional methionine (normally a mixture of D and L isomers), enabling the animal to synthesize additional cysteine through the transsulfuration pathway. There is increasing evidence that the experimental outcome depends on the precise formulation of the experimental diet. When both the high- and low-protein diets contain a supplement of 0.5% DL-methionine, the ratio of methionine to other amino acids is higher in the low-protein diet. Thus, one diet formula increases blood pressure in the offspring, whereas another different formula does not (31). It has been suggested that differences in the level of methionine supplementation may be one of the important factors.
Feeding low-protein diets with an imbalance in methionine throughout gestation results in offspring that remain smaller for the rest of their postnatal life, demonstrating a long-lasting effect of amino acid balance on postnatal growth (32). Although the relative intake of methionine is increased in the animals fed the low-protein diet, there is no change in the concentration of circulating methionine, suggesting that the control mechanisms are able to maintain homeostasis (33). However plasma homocysteine concentrations are increased in the low-protein groups, indicating a change in flux through the methionine cycle (34,35). There are increases in the global methylation of DNA in some of the fetal organs, which are consistent with a perturbation of SAM levels (34). Recent studies suggest that feeding the low-protein diets during gestation also produced specific changes in the methylation and expression of the glucocorticoid receptor and peroxisomal proliferator-activated receptor-
genes in the offspring. These changes persist after birth and are reversed by supplementing the maternal diet with additional folic acid (36). The products of both of these genes play an important role in metabolic regulation, and it is possible that epigenetic regulation of their expression is part of the programming mechanism. However, specific changes in methylation do not appear to be a universal feature because the methylation of the DNA coding for glucokinase, another key gene implicated in metabolic programming, is unaffected by feeding a low-protein diet during gestation (37).
The highest levels of homocysteine are found during the early stages of gestation. This may have a bearing on an interesting series of experiments in which animals were exposed to the low-protein diet for just the first 4 days of gestation, that is, during the preimplantation period. The offspring of these animals went on to exhibit increased blood pressure in adult life (38). It is possible that sudden changes in methionine intake may temporarily exceed the protective capacity of the homeostatic mechanisms, producing a brief disruption of preimplantation development that has long-term consequences.
In addition to epigenetic changes, the supply of glycine may also be an important factor mediating changes in the cardiovascular physiology of the offspring. Supplementing the low-protein diet with additional glycine can reverse the increase in blood pressure caused by feeding the low-protein diet (6). It appears that additional glycine improves vascular function of both dam and offspring. It has been suggested that the dam fed a glycine-supplemented diet is better able to adapt its vasculature to the demands of pregnancy, protecting the fetus from abnormal programming caused by a restriction in the uterine blood supply (39). Excess methionine in the maternal diet may also cause indirect effects on fetal development through subtle changes in endocrine parameters. For example, diets containing excess methionine may increase glucocorticoids or change levels of progesterone (13).
Semisynthetic diets based on casein are also devoid of components that can be synthesized from SAM, including taurine polyamines and choline. The de novo synthesis of these components is likely to increase the demand for methionine, masking the adverse effects of any excess. There are also likely to be radical changes in flux through the methionine cycle as animals fed diets prepared from purified components have to synthesize products absent from the diet. Taurine is the most abundant free amino acid in the body and the end product of methionine metabolism. Concentrations in the sera of dam and offspring increase markedly during the fetal and early postnatal periods of development; however, this does not occur to the same extent when animals fed the low-protein diet (40). Taurine deficiency adversely affects the development of the endocrine pancreas, an effect that is reversed by supplementing the low-protein diet with taurine (40). However, taurine supplementation appears to be detrimental to other aspects of fetal development, cautioning against its use to improve islet function (41,42). Polyamines are the other methionine-derived metabolite required for normal cell growth and absent from semisynthetic diets. During gestation, polyamines are essential for placental growth and angiogenesis (43). Hepatic spermine synthase is sensitive to excess methionine feeding, although methionine toxicity does not appear to be mediated by defective polyamine metabolism (44). At present there is little information on the impact of dietary methionine on polyamine synthesis during gestation.
Methionine intake in pregnancy: implications for humans. Analysis of extraembryonic coelomic fluid and amniotic fluid shows that concentrations of methionine are relatively high compared to the maternal circulation, suggesting that there is a role for methionine metabolism during early human pregnancy (45). However, there is very little information on the impact of changes in the composition of the maternal diet and, in particular, the effects of excess. As with the animal studies, the associations between methionine intake and adverse outcomes are complicated by the metabolic interactions of the methionine cycle. The role of folate supplementation in reducing the risk of neural tube defects (NTD) is well documented, suggesting an association between methionine metabolism and the NTD risk. Women with the lowest average daily dietary intake of methionine (>1580 mg/d) had a greater risk of carrying a fetus affected by NTD (46). Methionine levels in the amniotic fluid of NTD-affected fetuses were also lower than those in corresponding controls (47). Other components of the methionine cycle also influence the NTD risk, which was lowest for women whose diets were rich in choline, betaine, and methionine (48). Despite this epidemiologic evidence, there is no clear mechanistic link between methionine metabolism and NTD risk in humans.
In conclusion, the role of dietary methionine and the long-term impact of perturbed methionine metabolism during gestation are still poorly understood in humans. Methionine intakes in human diets have steadily increased in the last century. Animal studies suggest that there is a potential for adverse effects of excessive intakes, mediated though changes in glycine metabolism and the perturbation of methylation reactions. Excessive dietary methionine may also influence fetal development indirectly through homocysteine or perturbation of endocrine functions. However, in all cases the present knowledge on the impact of excessive dietary methionine during gestation is very limited, and further studies are needed to define the upper safety level of intake. In particular it is important to bear in mind that the role of other diet components can alter this value, and caution should be exercised in any attempt to supplement the diets of pregnant women with additional methionine.
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FOOTNOTES |
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2 Work in the authors' laboratory was supported by the Scottish Executive Environment and Rural Affairs Department as part of the core funding of the Rowett Research Institute. Christopher Maloney is supported by a cooperative agreement from the National Institutes of Health (U01 HD044638 to Kevin Sinclair) as a component of the NICHD Cooperative Program on Female Health and Egg Quality.
4 Abbreviations used: NTD, neural tube defect; PC, phosphatidyl choline; PEMT, phosphatidyl ethanolamine methyl transferase; SAHcy, S-adenosyl homocysteine; SAM, S-adenosyl methionine.
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