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The Rowett Research Institute, Bucksburn, Aberdeen, AB21 9SB, Scotland
2To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • rats • pregnancy • cysteine • methionine • threonine • homocysteine • folate
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Hales and Barker 1992
). This phenomenon is not confined to humans; feeding
pregnant rats diets moderately deficient in protein has a similar
effect, programming the adult blood pressure and glucose metabolism of
the offspring (Desai et al. 1995
, Langley and Jackson 1994
). A diet containing 9% protein is still able to
support pregnancy but produces an unusual pattern of fetal growth
compared with a control diet containing the optimum of 18% protein.
Initially, there is an apparent increase in fetal growth; by d 19, the
fetuses of protein-deficient dams are ~7.5% larger than the
controls. However, this is not sustained, and by d 21 of the 22.5-d
gestation period, the average fetal weight is ~15% less than that of
the control (Langley-Evans et al. 1996a
, Rees et al. 1999a
). The serum concentrations of most essential amino
acids are unchanged. L-Threonine is the only essential
amino acid that changes significantly; both maternal serum
concentrations and fetal body pools fall to less than half of those
found in rats fed a control diet (Rees et al. 1999a
).
These changes in threonine metabolism may be linked to the abnormal
fetal growth.
Pregnant rats fed a protein-deficient diet may be unable to
maintain normal threonine concentrations either because of a failure in
the supply or an increase in demand. If the dam is unable to compensate
for the reduction in the dietary intake by mobilizing sufficient
threonine from body proteins, then the circulating concentrations will
fall. This is easily tested by feeding pregnant rats low protein diets
supplemented with additional threonine. An increase in the metabolic
demand for threonine will also reduce concentrations in the
circulation; the two possible routes of threonine metabolism are shown
in Figure 1
. It can be deaminated by the enzyme threonine-serine dehydratase
(EC 4.2.1.16:
TDH)3
to yield 2-ketobutyric acid which is then oxidized to
CO2. Alternatively, L-threonine
3-dehydrogenase (EC 1.1.1.103; TDG) converts it to
2-amino-3-ketobutyrate, which is then cleaved to yield glycine +
acetyl-CoA. It can be seen from Figure 1
that both pathways of
threonine oxidation are linked to the metabolism of methionine. If
growing male rats are fed a diet containing an excess of methionine,
there is an increase in the rate of transulfuration; this induces
threonine-serine dehydratase, causing plasma threonine levels to
fall (Girard-Globa et al. 1972
). The change in free
threonine levels in pregnant rats fed a low protein diet may therefore
be linked to the metabolism of methionine.
|
and 1995
). A wide variety of cellular methylation
reactions including changes in global DNA methylation are dependent on
SAM and SAHcy (Wainfan and Poirier 1992
). In adult rats,
the extent of DNA methylation depends on the composition of the diet
(Pogribny et al. 1995
). Therefore, maternal homocysteine
metabolism may influence the levels of DNA methylation in the fetus. To
address the metabolic interactions among threonine, homocysteine and
DNA methylation in fetal development, we fed pregnant rats low protein
diets supplemented with additional threonine. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The experimental diets were identical to those described by
Langley-Evans et al. (1996a)
. The control (18% casein)
diet contained the following (g/kg): casein, 180; sucrose, 213;
cellulose fiber (solkaflok) 50; cornstarch, 425; vitamin mix AIN-76
(AIN 1977
), 5; mineral mix AIN-76, 20; corn oil, 100;
choline chloride, 2; and DL-methionine, 5. The low protein
diet (9% casein) contained only 90 g/kg casein, with compensating
increases in the amounts of sucrose and cornstarch (1:3). The low
protein diet supplemented with threonine was based on the same mixture
but contained only 8% protein supplemented with 1 g/100 g
L-threonine (Ajinomoto, Tokyo Japan). Choline chloride and
methionine were from Sigma (Poole, Dorset, UK); the other ingredients
were from Special Diet Services (Witham, Essex, UK).
Experimental animals.
Female rats of the Rowett Hooded Lister strain from the Institute’s breeding colony were fed the experimental diets beginning at 6–7 wk of age. Two weeks later, when they weighed ~230–240 g, the rats were mated with males of the same strain. Mating was confirmed by detection of a vaginal plug and this was denoted d 0. The female rats consumed the same diets throughout pregnancy. In two separate experiments, three groups each of eight rats were fed one of the three diets until d 21 of pregnancy. Some rats were injected via the tail vein with 1.85 MBq L-[U-14C]threonine (8.1 GBq/mmol; ICN Biomedicals Basingstoke, Hants, UK) 1 h before killing. Adult rats were killed by stunning and exsanguination; the fetuses were weighed and killed by decapitation. All experimental procedures were approved and conducted in accordance with the UK Animals (Scientific Procedures) Act, 1986.
Sample collection and analysis.
Organs (liver, kidney, heart and brain) of up to eight fetuses, chosen
from each dam at random, were rapidly dissected and weighed. Samples
were frozen rapidly in liquid nitrogen and subsequently stored at
-70°C. To measure total fetal amino acids, one whole fetus was
chosen at random from each dam, homogenized in 2 mL of distilled water,
and proteins were precipitated by the addition of 1 mL of 2 mol/L
perchloric acid. Nor-Leucine (100
µmol/L) was added to all samples to act as an external
standard. Details of the amino acid analysis have been given previously
(Rees et al. 1999a
). Homocysteine was measured by the
method of Briddon (1998)
. Within 5 min of collection,
samples of maternal and pooled fetal plasma were treated with 1.2%
(v/v) dithiothreitol for 2–5 min, deproteinized with sulfosalicylic
acid (final concentration 7%) and analyzed on a Pharmacia Alpha Plus
amino acid analyzer (Amersham Pharmacia Biotech, Little Chalfont,
Bucks, UK). The column was operated in the lithium form, and amino
acids were eluted in a stepwise series of lithium citrate buffers and
detected with ninhydrin.
Threonine oxidation by liver homogenates.
Maternal livers were removed, weighed and 1- to 2-g samples were
homogenized in 2 mL of cold buffer [0.25 mol/L sucrose, 10 mmol/L Tris
HCl (pH 7.4) and 1 mmol/L EDTA] per gram of tissue. Debris was removed
by centrifugation at 800 x g for 5 min at 4°C.
Aliquots of the homogenate (200 µL) were mixed with
100 µL of buffer containing unlabeled threonine and
100 µL of buffer containing 1.48 kBq
[U-14C] L-threonine (ICN Biomedicals
Basingstoke,) or L-[U-14C]-homoserine
(Rees et al. 1994
). A small tube containing 0.1 mL of 5
mol/L NaOH dispersed over a paper wick was suspended from the rubber
stopper used to seal the tube. The reaction was incubated for 2 h
at 37°C in a metabolic shaker and terminated by injecting 0.5 mL of 2
mol/L H2SO4 through the stopper with a
hypodermic syringe. The tubes were returned to the shaker for 2 h.
The small tube was then removed, and radioactivity trapped in the NaOH
was determined by scintillation counting in 5 mL of Ultima Gold XR
scintillant (Packard Bioscience B.V. Groningen, The Netherlands).
Homogenates were incubated with a range of threonine concentrations
from 0.5 to 20 mmol/L. The rates for each concentration were determined
from the linear part of the progress curve, and an apparent
Vmax for each tissue homogenate was
determined from reciprocal plots of these data. Protein concentrations
were determined by the method of Lowry et al. (1951)
.
DNA extraction.
Tissue (~100 mg) was powdered under liquid nitrogen and suspended in
7 mL of extraction buffer [10 mmol/L Tris-Cl, pH8.0, 0.1 mol/L
EDTA, 5 g/L (wt/v) SDS] containing 20 mg/L RNase and 100 mg/L
proteinase K (Michalowsky and Jones 1989
). The sample
was incubated for 12–18 h at 55°C and then extracted three times
with water-saturated phenol. DNA was then precipitated from the
aqueous phase by the addition of 0.1 volume of 2 mol/L ammonium acetate
and 2 volumes absolute ethanol. The sample was then redissolved in TE
buffer [10 mmol/L Tris-Cl (pH 8.0), 1 mmol/L EDTA] and dialyzed
for 48 h against 100 volumes of TE buffer. DNA was quantified by
reading the absorbance at 260 nm.
DNA methyl transferase assay.
The extent of CpG methylation was ascertained using the assay of
Balaghi and Wagner (1993)
. Briefly, 0.5
µg of genomic DNA was incubated in a
30-µL volume containing 3 µmol/L (74
kBq) [3H-methyl]S-adenosyl methionine (NEN
Stevenage, Herts, UK), 3 µL of the 10X reaction buffer
and 3 U of SssI DNA methylase (New England
Biolabs, Hitchin, Herts, UK). The reaction was incubated at 30°C for
1 h. Aliquots (15 µL) of the reaction mixture
were spotted onto DE81 paper circles (Whatman, Maidstone, Kent, UK),
washed five times in 0.5 mol/L sodium phosphate buffer (pH 6.8) and
dried in air; the remaining radioactivity was determined by liquid
scintillation counting. Blank values were determined from duplicate
incubations without enzyme. The reaction had reached its end point
within 30 min, and the radioactivity incorporated per microgram of DNA
was independent of the amount of DNA present in the reaction mixture.
Statistical analysis.
Mean values were calculated for all of the pups and placentae. Previous
work with the same strain of rats has not shown any correlation between
fetal number and fetal weight (Palmer et al. 1996
).
Fetal organs were dissected from up to eight fetuses chosen at random
from each dam. The data in Tables 1
2
3
4
were analyzed by one-way
ANOVA followed by a Tukey multiple comparison test. Data were processed
using the Instat statistical package (GraphPad Software, San Diego,
CA). For the measurements of threonine in Table 2
, the variation among
fetuses was clearly greater in the supplemented group than in the other
two groups. ANOVA was therefore inappropriate for these groups and a
two-sample t test was used instead. Values are means
± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). In the group fed the diet containing 8% casein supplemented with
threonine, fetal weights were 9.1% lower than the controls,
significantly smaller (P = 0.049) than the group fed
the 18% casein diet but not significantly different from those in the
group fed the 9% casein diet. This was also the case for individual
fetal organs. The weights of livers, kidneys, hearts and brains in the
group fed the diet containing 8% casein supplemented with threonine
were significantly lower than those of the control group but not
significantly different from those of the group fed 9% casein. The
placental weights were not affected by protein deficiency or threonine
supplementation.
The free threonine concentrations in the fetuses of rats fed the diet
containing 9% casein were 31% lower than those in the group fed the
diet containing 18% casein (Table 2
, P = 0.027, by Student’s t test). A similar
pattern of differences in free threonine was also observed in the
maternal serum (data not shown). Except for increases in glycine and
phenylalanine, maternal protein deficiency did not affect the
concentrations of other essential amino acids in the fetus. These
results are largely consistent with our previous data (Rees et al. 1999a
). Free threonine concentrations in the fetuses of
dams fed the diet containing 8% casein supplemented with threonine
were three times those of the fetuses from dams fed 18% casein (Table 2)
. In the fetuses of the group fed the diet containing 8% casein
supplemented with threonine, the free concentrations of methionine and
tryptophan were 53 and 58%, respectively, of the levels found with the
18% casein control diet. There were also smaller differences in most
of the other essential amino acids.
In a preliminary experiment, a single rat from each group was injected with L-[U-14C]threonine and killed after 1 h. In all three rats, radioactivity in the maternal serum free amino acid pool and in liver protein was associated almost exclusively with threonine; only 0.02% of the total radioactivity was associated with glycine in the liver proteins and <0.1% was associated with glycine in the free amino acid pool. There was also an unidentified product in the maternal serum, which was not retained by the column of the amino acid analyzer and eluted in the void volume. The characteristics of the unknown product were similar to those of a ketoacid, suggesting that threonine was being oxidized by the maternal liver.
Liver homogenates from nonpregnant rats oxidized
L-[U-14C]threonine to
14CO2 by a saturable
process with an apparent Km of 13.4
mmol/L (Fig. 2A
), which was inhibited by homoserine with an apparent
Ki of 3.6 mmol/L (Fig. 2B
).
When radiolabeled homoserine was used as the tracer, the apparent
Km for oxidation was found to be 1.3
mmol/L (Fig. 2C
), and threonine inhibited with a
Ki of 11.2 mmol/L (Fig. 2D
). The oxidation of threonine and homoserine was also
strongly inhibited by cystathionine, another intermediate in the
transulfuration pathway with a Ki of
0.1 mmol/L (data not shown). This is consistent with threonine,
homoserine and cystathionine sharing a common oxidative pathway through
threonine-serine dehydratase. The rate of threonine oxidation by
homogenates of the livers of nonpregnant rats fed a diet containing
18% casein was 67.2 ± 7.9 pmol/(min · mg protein)
(n = 4). By d 21 of pregnancy, this rate had fallen to
18.0 ± 0.1 pmol/(min·mg protein). Homogenates prepared from the
livers of dams fed the diet containing 9% casein oxidized threonine at
a significantly higher rate, nearly twice that of rats fed the diet
containing 18% casein (Table 3
). The rate of threonine oxidation by liver homogenates from the rats
fed the diet containing 8% casein supplemented with threonine did not
differ from that of rats fed the diet containing 18% casein when
expressed per milligram protein. However, the
threonine-supplemented diet caused a significantly greater liver
weight (Table 3)
. Thus, when expressed per total liver, the total
activity was ~40% greater than in rats fed the diet containing 18%
casein.
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. However, maternal serum
homocysteine concentrations were significantly greater by 65% in the
dams fed the diet containing 8% casein supplemented with threonine.
Homocysteine concentrations in fetal serum were lower than those in
maternal serum and were not affected by the protein content of the
maternal diet or by threonine supplementation.
Treating genomic DNA with SssI methylase and
[3H-methyl]-SAM, incorporates
[3H]-methyl groups into unmethylated cytosine
residues of CpG sites in the DNA. Therefore, there is a reciprocal
relationship between the incorporation of label and the extent of
endogenous methylation. The incorporation of radioactivity into the
livers of fetuses from dams fed the diet containing 9% casein was 22%
lower (P < 0.05) than in the fetuses of dams fed the
diet containing 18% casein (Table 4
). This indicates that the extent of endogenous DNA methylation in the
livers of fetuses from dams fed the low protein diets was greater than
in the control. In dams fed the diet containing 8% casein supplemented
with threonine, incorporation was further reduced (P < 0.05), to 67% of that found in the control, showing that the
endogenous DNA methylation was even greater in this group. These
differences were confined to the liver; methylation of DNA from the
kidneys and hearts of these fetuses was not significantly different
from the controls.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), free threonine concentrations in the fetus were lower
when pregnant rats were fed a protein-deficient diet. Supplementing
the low protein diet with additional threonine failed to restore fetal
growth, and the fetuses were similar in weight to those fed the low
protein diet alone, suggesting that the threonine supply is not
limiting for growth. However, the excess threonine inhibited the uptake
of other amino acids; therefore, in the fetuses from dams fed the
threonine-supplemented diets, there were effects on most of the
essential amino acids. The largest differences were in methionine and
tryptophan (53 and 58% of the control, respectively) with much smaller
differences in valine and isoleucine (83 and 72% of the control,
respectively). Studies of pregnant rats fed diets devoid of single
essential amino acids have shown that fetal growth is most sensitive to
deficiencies of methionine, valine and isoleucine (Niiyama et al. 1973
). Thus, it is possible that any improvement in
fetal growth resulting from a restoration of the threonine supply was
masked by a deficiency of methionine. However, this is unlikely because
the growth of fetuses from dams fed a diet containing 15% lactalbumin,
without supplementary methionine, is comparable to the growth of those
fed 18% casein despite a methionine concentration of 87.2 ± 3.9
nmol/g (unpublished data).
The casein-based diets used in these experiments are similar to
those used in a number of other laboratories to demonstrate the
development of hypertension and impaired glucose tolerance in the
offspring of female rats fed protein-deficient diets (Desai et al. 1995
, Holness and Sugden 1996
,
Langley-Evans et al. 1996a
, Snoeck et al. 1990
). Unfortunately, casein provides less than half of the
cysteine required by rats during gestation (Reeves et al. 1993
). To compensate, extra methionine is added to the diet so
that rats can produce cysteine by transulfuration of homocysteine (Fig. 1)
. Cystathionine and homoserine, by-products of cysteine
synthesis, share the same oxidative pathway as threonine; therefore the
induction of transulfuration increases threonine oxidation
(Girard-Globa et al. 1972
). The present results confirm
that this same mechanism is operating in pregnant rats; the change in
threonine oxidation is an indirect consequence of the change in
methionine metabolism. The situation is further complicated because the
same methionine supplement (5 g/kg) is added to both the low and high
protein diets, supplying the protein-deficient rats with an excess
of methionine relative to other amino acids. Supplementing the low
protein diet with extra threonine increases circulating homocysteine
because it is a competitive inhibitor of homoserine oxidation.
Supplementing protein-deficient diets with taurine reverses the
effects of protein deficiency on insulin release by pancreatic islet
cells (Cherif et al. 1998
). Taurine is derived from
cysteine and is particularly important during fetal development.
Supplementing with taurine, as well as helping to meet the requirement,
will also reduce the demand for cysteine. This in turn will lessen the
flux through the transulfuration pathway and reduce total homocysteine
production. It is also important to note that the metabolism of
methionine is influenced by endocrine factors such as the
glucocorticoid hormones (Finkelstein et al. 1978
). It
has been suggested that maternal glucocorticoids crossing the placenta
are an important regulator of fetal development (Benediktsson et al. 1993
), and experiments in rats have shown that
pharmacologic interventions that alter glucocorticoid status can mimic
the effects of protein deficiency (Langley-Evans et al. 1996b
). Because these experiments were conducted using
casein-based diets, it is possible that changes in sulfur amino
acid metabolism may have been involved in the effects observed.
Comparatively small increases in the levels of homocysteine have
adverse effects on a number of other physiologic systems, particularly
endothelial cell function (Selhub 1999
). In humans,
elevated levels of homocysteine are associated with obstetric
complications including preeclampsia, neural tube defects and recurrent
miscarriage (Wouters et al. 1993
). The mechanisms are
unknown but may be related to disturbed fetal metabolism
(Malinow et al. 1998
). Because the fetus lacks
cystathionine ß-synthase, its only means of eliminating homocysteine
is through the synthesis of S-adenosyl homocysteine, which
is then remethylated to SAM (VanAerts et al. 1995
). When
d-11 rat embryos are cultured ex utero in media containing excess
homocysteine, SAM levels are increased, stimulating growth
(VanAerts et al. 1994
), a result that may explain the
early increase in fetal growth seen in pregnant rats fed
protein-deficient diets (Langley-Evans et al. 1996a
,
Rees et al. 1999a
). The remethylation of
S-adenosyl homocysteine also increases the demand for methyl
groups derived from tetrahydrofolate, reducing the availability of
folates for deoxynucleoside triphosphate synthesis (James et al. 1992
). Genes such as p53, which are involved in the response to
nucleotide deficiency, are more highly expressed in immature organs
(Rees et al. 1999b
). The effect of restricting the
supply of nucleotides and causing a delay in DNA synthesis is unknown,
but this simple growth arrest may be sufficient to program subsequent
development.
Cell culture experiments suggest that the fetal programming of
adult metabolism is not simply a consequence of altered cell growth.
Isolated cells continue to show a permanent change in their function.
For example, pancreatic islets from the offspring of
protein-deficient animals release less insulin (Cherif et al. 1996
), and there are changes in the insulin signaling
system of isolated adipocytes (Ozanne et al. 1997
). The
current experiments show genome-wide changes in DNA methylation,
which are apparently confined to the liver. These changes are similar,
however, to those seen in adults whose level of DNA methylation can be
altered by diet-induced changes in homocysteine and folate status
(Jacob et al. 1998
).It is possible that these changes
may include cytosine residues important for the regulation of specific
genes. For example, there are well-characterized changes in the
methylation of the insulin-like growth factor II gene, which lead
to a loss of imprinting and fetal oversize in mice (Leighton et al. 1995
). It remains to be seen whether such highly specific
changes in DNA methylation can be caused directly by alterations in the
SAM pool.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: SAHcy, S-adenosyl homocysteine; SAM, S-adenosyl methionine; TDG, L-threonine 3-dehydrogenase; TDH, L-threonine-serine dehydratase.
Manuscript received November 4, 1999. Initial review completed December 14, 1999. Revision accepted March 22, 2000.
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