LEUKOCYTES
AND
FETAL
MALNUTRITION
EUKOCYTES are among the few cells of
human origin that can be relatively
easily obtained from the living subject. For
this reason, they have been periodically
used to measure the tissue status of
en-zymes, metabolites, and essential nutrients
such as vitamin C. Some years ago, Metcoff
and his colleaguesl2 related changes in the
energy metabolism of leukocytes to the
de-gree of postnatal malnutrition of young
children. They were able to demonstrate a
deficit in the capacity for generation of
ade-nosine triphosphate
(
ATP)
in the leukocytesof infants with protein-calorie malnutrition
and correlated this with reduced activities
of the enzymes pyruvate kinase and
adeny-late kinase which are involved in the
me-tabolism of ATP formed by glycolysis, the
predominating energy-generating process
in leukocytes.
In the present and preceding issues of
PimIAmIcs, Metcoff and his coworkers36
have extended these studies to children of
low birth weight due either to prematurity
without growth failure
(
the “appropriatefor gestational age” group [ACAJ
)
or tofe-tal growth retardation
(
the “intrauterinemalnutrition” group [IUM]
).
In these twogroups and in a third group of full-term
healthy infants
(
FT), they have mademea-surements on fetal leukocytes
(
cord blood),maternal leukocytes and the placenta, which
indicate their capacity to generate energy
and in some instances to synthesize RNA
and protein. In the infants with intrauterine
malnutrition the fetal leukocytes were
larger than those of the other two groups
but had a low content per cell of ATP and
of pyruvate kinase and adenylate kinase.
Thus, they resembled the leukocytes of
in-fants malnourished tn’2 in having
a low capacity to generate energy. This
contrasts with the leukocytes of infants of
low birth weight due to prematurity
(ACA group
)
which showed no reductionin ATP content or pyruvate kinase activity
although adenylate kinase activity was
somewhat low.
The leukocytes of the mother were also
found to undergo changes during
preg-nancy.6 Studies during the last eight weeks
of gestation showed a considerable increase
in adenine nucleotide content per cell,
par-ticularly ATP and adenosine diphosphate
(
ADP), and this was accompanied byin-crements in pyruvate kinase and adenylate
kinase activities. This implies that the
“en-ergy capacity” of maternal leukocytes
in-creases as pregnancy progresses. Among the
mothers of progeny malnourished in utero,
however, the ATP content of their
leuko-cytes was high but the activity of adenylate
kinase was reduced, so that the energy
ca-pacity of the maternal cells, like that of the
fetal cells, was low. This, coupled with the
larger size of both maternal and fetal
leuko-cytes in intrauterine malnutrition, sets that
group apart from those whose low birth
weight was due to prematurity alone
(ACA
group
)
. However, this distinction did nothold when the capacity of maternal
leuko-cytes to synthesize RNA was measured. In
normal pregnancy, the RNA polymerase
system undergoes a modest increase in
ac-tivity per leukocyte during the last ten
weeks of pregnancy, but was less active in
mothers in both the IUM and ACA group.
It would thus seem that, while enlarged
maternal leukocytes with low energy
capac-ity are characteristic of intrauterine
malnu-trition, low RNA polymerase levels in
ma-ternal leukocytes are associated with low
birth weight from all causes.
One might suspect that the placentas of
malnourished fetuses would also show
simi-lar evidence of an inferior capacity to
gen-erate energy. However, ATP and adenylate
kinase content per unit of DNA were not
lower in those placentas, whereas both
were much reduced in placentas of infants
small because of prematurity.5
Further-more, the RNA polymerase activities of
both IUM and ACA placentas were higher
per unit of DNA,C which may correlate with
the tendency to have a greater amount of
RNA per cell,5 and with the increased
COMMENTARIES
pacity of placental ribosome complexes
(
polyribosomes)
from both IUM and AGAcases to make peptide bonds in vitro. This
implies that the smaller placentas of these
two groups may have been compensated by
developing an increased capacity per unit
of weight for RNA and protein synthesis.
Fetal growth retardation affects about
3% of births in developed countries and up
to 10% in developing countries where
ma-ternal malnutrition may
be
a majorcontrib-utory factor. Such underdeveloped infants
have small organs and display a high
fre-quency of congenital defects, mental
defi-ciency and subsequent delayed growth
pattern.7 It is, therefore, of considerable
in-terest to have a potential predictive test in
the form of changes in maternal leukocyte
size and energy metabolites. Since
leuko-cytes are a mixture of several cell types, it
will be a matter for future investigation to
determine whether the changes associated
with intrauterine malnutrition are due to a
shift in the proportions favoring those cell
types with a large ratio of cytoplasm to
flu-cleus (protein/DNA ratio) but a low
ca-pacity for energy generation. Such
investiga-lions may simplify the identifying features
of the leukocyte change so that it no longer
requires technically complex assays.
The significance of these investigations in
understanding the causes of fetal growth
retardation is less clear. The resemblance of
the fetal leukocyte changes in IUM to those
observed in postnatal dietary malnutrition
may justify the conclusion that intrauterine
growth retardation is also due in many
cases to an inadequate supply of nutrients.
The relationship to placental function is
more complex. Although the IUM placentas
are smaller, they retain a normal capacity
for energy generation and their smaller size
is compensated by an increased capacity for
with the placentas of women in Boston.
However, this biochemical observation hid
a striking deficit in trophoblast mass which
became apparent when the Cuatemalan
se-ries of placentas were subjected to
quanti-tative morphological assessment.9 The
pla-centa is a complex organ of which the
trophoblast accounts for only a small part.
It may, therefore, be too early to try to assess
the role of changes in placental
biochemis-try in relation to fetal growth retardation
and to maternal responses to the state of
development of the fetus. It is nevertheless
very encouraging to have biochemical
pa-rameters responsive in the mother and fetus
to intrauterine growth retardation, and we
may look forward to a more profound
un-derstanding of the mechanisms involved in
the production of this very important
syn-drome.
HAMISH N. Muro, M.B., D.Sc.
Massachusetts Institute of Technology
Cambridge, Massachusetts
REFERENCES
1. Yoshida, T., Metcoff,
J.,
Frenk, S., and de IaPena, C. : Intermediary metabolites and
ade-nine nucleotides in leukocytes of children with protein-calorie malnutrition. Nature, 214:
525, 1967.
2. Yoshida, T., Metcoff,
J.,
and Frenk, S.:Reducedpyruvic kinase activity, altered growth
pat-terns of ATP in leucocytes, and
protein-cab-rie malnutrition. Amer.
J.
Clin. Nutr., 21:162,1968.
3. Urrusti,
J.,
Yoshida, P., Velasco, L., Frenk, S.,Rosado, A., Sosa, A., Morales, M., Yoshida, T.,
and Metcoff,
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: Human fetal growthretarda-tion. I. Clinical features of sample with
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A., Sosa, A., Yoshida, P., Urrusti,
J.,
Frenk, S.,and Vebasco, L. : Human fetal growth
retarda-tion. II. Energy metabolism in beukocytes.
928 LEUKOCYTES AND FETAL MALNUTRITION
Frenk, S., Madrazo, R., and Velasco, L.: En- 8. Laga, E. M., Dniscoll, S. C., and Munno, H. N.
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