ARTICLE
Auteur(s) : Hans Demmelmair1, Elvira
Larque2, Berthold
Koletzko1
1Labor für Stoffwechsel und Ernährung, Dr. von Hauner
Children’s Hospital, Ludwig-Maximilians University of Munich,
Lindwurmstr. 4, D-80337 Muenchen, Germany
2Department of Animal Physiology, Biological Faculty,
University of Murcia, Spain
Introduction
There is considerable evidence that the supply of long-chain
polyunsaturated fatty acids (LC-PUFA) during pregnancy and the
early postpartal period is of importance for growth and nervous
system development. The LC-PUFA arachidonic (AA, 22:4 n-6) and
docosahexaenoic acid (DHA, 22:6 n-3), are deposited in relatively
high concentrations in developing neural cells, and they modulate
the structure, fluidity and function of brain membranes [1]. The
importance of brain DHA is mainly related to its significant roles
in maintaining neurological and visual development. Decreased DHA
contents in brain and retina lipids result in altered visual
acuity, disturbance in electroretinographic measurements and
learning impairment in various species [2]. AA is a major component
of structural phospholipids and serves as precursor for
eicosanoids, which play important roles in cell division, signal
transduction and many other physiological processes [3]. In preterm
babies the availability of AA has been associated with weight at
birth and growth during the first year of life [4]. Here we discuss
some ideas about the mechanistic principles of the LC-PUFA transfer
from the mother to the foetus via the placenta during pregnancy and
its effect on the development of neural functions is addressed
briefly.
LC-PUFA supply in the perinatal period
LC-PUFA of the n-6 and n-3 series are derived from the essential
fatty acid precursors linoleic acid (n-6) and α-linolenic acid
(n-3) by consecutive enzymatic desaturation and chain elongation
[5]. LC-PUFA are incorporated into practically all tissues of the
foetus and infant, and they are the predominant PUFA in mammalian
brain and neuronal tissues [2]. In humans, most brain LC-PUFA are
accumulated during the phase of rapid brain growth in the last
trimester of gestation and the first 2 years after birth. Although
the conversion of LC-PUFA from the essential fatty acid has been
demonstrated in neonates [6], as other lipids they have to be
transferred across the placenta to meet fetal demands [3]. The
foetus needs to receive appreciable amounts of preformed AA and DHA
by placental transfer to meet LC-PUFA accretion rates in membrane
rich tissues.
The accumulation of brain DHA and AA from dietary preformed DHA
and AA is far more efficient than the accumulation from dietary
essential fatty acid precursors and their endogenous desaturation
and elongation. It is estimated that about half of postnatal brain
AA accretion is derived from dietary preformed AA in term baboon
neonates [7], while fetal plasma DHA is about 8-20 fold more
effective as a substrate for brain DHA accretion in fetal baboons
compared with α-linolenic acid [8]. Fetal LC-PUFA status depends on
maternal intake, which has been demonstrated by an increase of cord
blood DHA after maternal DHA supplementation during pregnancy [9,
10]. On the other hand also the efficiency of the transfer seems to
be an important factor, as differences in polyunsaturated fatty
acid fetal-maternal relationships between appropriate for
gestational age and intrauterine growth restricted foetuses have
been observed [11].
Placental transfer of fatty acids
Numerous studies reported significant differences between the fatty
acid composition of maternal plasma lipids at the time of delivery
and cord plasma lipids. Percentages of saturated and
monounsaturated fatty acids are very similar between maternal
plasma phospholipids and cord blood phospholipids. On the other
hand essential fatty acid percentages are significantly lower in
cord blood phospholipids, which is accompanied by clearly increased
LC-PUFA percentages [12]. These observations point to a
preferential transfer of LC-PUFA by the placenta. This agrees with
an in vitro observation after the incubation of immortalized
trophoplast cells (BEWO) with radio labelled fatty acids [13].
After incubating BEWO cells in 200 μM solutions of oleic acid,
linoleic acid, AA or DHA, respectively, at 37 °C applying a
fatty acid albumin ratio of 1:1 they found the highest cellular
uptake for DHA and the lowest for oleic acid, while linoleic acid
and AA were similar intermediate between the other studied fatty
acids.
Using stable isotope labelled fatty acids we investigated the
placental transfer in vivo in humans [14]. Palmitic-, oleic-,
linoleic- and docosahexaenoic acids labelled with the natural
carbon variant 13C were administered orally 4 hours
before elective caesarean section to pregnant women. Tracer
concentration was analysed hourly in maternal blood samples until
delivery, in cord blood and in placental tissue. The time course of
tracer concentration in maternal samples can be considered an
indicator of the availability of the tracer for placental transfer,
thus the amount potentially available for transfer. On the other
hand, the tracer concentration in placental tissue and cord blood,
respectively, indicate the amount, which has been transferred out
of the maternal compartment into placenta or foetus, respectively.
This has been related to the tracer concentration in the mother and
the quotient obtained can be considered indicative for the transfer
intensity of individual fatty acids. These quotients were not
different between fatty acids, if cord blood tracer was related to
the maternal compartment, but corresponding quotients for the ratio
between placental tissue and maternal circulation were 7.1 ± 1.0%
(M±SEM, n = 4) for palmitic acid, 3.8 ± 0.4% for oleic acid, 9.2 ±
1.3% for linoleic acid and 25.9 ± 3.4% for DHA, which was
significantly higher than for the other fatty acids [14]. Although
these percentages do not correspond to the real amount transferred,
as this would require the inclusion of compartmental size into the
calculation, a comparison between the studied fatty acids is valid,
as compartmental size is the same for each of them. Thus it can be
deduced that incorporation of DHA into placental tissue is 3 to 7
times more intensive than for the other studies fatty acids (figure 1). Although
this can only be concluded for the time point studied (4 hours
after intake) it seems to be at least qualitatively representative
for the full process and the data agree with the in vitro
observation.
The placental transfer of fatty acids is considered a complex
process, which involves their binding to membrane proteins and
cytoplasmatic transport proteins [15]. It is known that placenta
takes up circulating non esterified fatty acids (NEFA) as well as
NEFA released from maternal circulating lipids by placental lipases
[16]. In addition, human placental tissue expresses receptors to
VLDL, LDL and HDL lipoproteins [17], which could provide fatty
acids to the placenta for transfer once they are released by
intracellular lipases although the significance of this mechanism
is still unknown.
NFA enter placental cells through both passive diffusion as well
as via carrier proteins. This transport mechanism seems to involve
plasma membrane fatty-acid binding protein (FABPpm/GOT2), fatty
acid translocase (FAT/CD36), fatty acid transport proteins (FATP),
and fatty acid binding proteins (FABP) [18]. Although the roles of
these proteins in placental fatty acid uptake and further
processing are not yet fully understood, it has been suggested that
the enrichment of LC-PUFA in the fetal circulation relative to the
maternal circulation is related to these proteins. A further fatty
acid binding protein located exclusively on the maternal-facing
membranes named placental plasma membrane fatty acid-binding
protein (p-FABPpm) has been proposed to be involved in
the preferential uptake of LC-PUFA by trophoplast cells [19]. After
the application of antibodies against placental plasma membrane
fatty acid binding protein the uptake of DHA and AA was
significantly more reduced than the uptake of oleic acid in BEWO
cells, which points towards the importance of this postulated
protein for a preferential uptake of LC-PUFA by the placenta [13].
However, definitive evidence about the structure and function of
p-FABPpm must await analysis of its complete amino acid and/or cDNA
sequence.
In the cytosol, fatty acids are esterified within the lipid
fractions of the placenta or cross the tissue in either direction
bound to cytosolic proteins. Also at this stage differences between
DHA and other fatty acids become obvious, as only a small portion
of DHA is found in the nonesterified fatty acids and in comparison
to AA incorporation of DHA into triacylglycerols is high [13].
Several FABP are involved in the fatty acid transfer to the
fetal circulation and so far heart-FABP (H-FABP) and liver-FABP
(L-FABP) and adipose tissue (A-FABP) have been identified in
placenta. However, the mRNA expression of other cytosolic FABPs
reported in other tissues might occur in placental tissue, which
should be confirmed in trophoblast cells since placenta samples
contain many cell types including a large content of blood
cells.
In a double blind randomized intervention trial healthy pregnant
women received during the second half of gestation supplements with
modified fish oil providing 500 mg DHA and 150 mg of
eicosapentaenoic acid per day with vitamins, or a placebo oil with
vitamins. This led to a significantly higher percentage of DHA in
the cord blood phospholipids of supplemented women (9.6 ± 2.2%
wt/wt vs. 8.4 ± 2.1% wt/wt) [9]. In a group of 136 study
participants the mRNA expression of various membrane bound and
cytosolic fatty acid carrier proteins, FAT/CD36, pm-FABP, A-FABP,
B-FABP, H-FABP, FATP-1, FATP-6 and FATP-4 was investigated [20].
DHA supplementation did not induce a significant difference between
groups in any of the fatty acid carriers, as might be expected from
the known influence of DHA on PPAR expression and the known
relationship between PPAR and some fatty acid carriers.
Nevertheless, among the whole studied population there were
significant positive correlations between the m-RNA expression for
FATP-1 and placenta phospholipid DHA percentage (r = 0.36, p <
0.001) and FATP-4 m-RNA expression and placental phospholipid DHA
(r = 0.39, p < 0.001). DHA percentages in placental
triacylglycerols correlated to FATP-1 and FATP-4 expression with
r-values of 0.37 and 0.47, respectively. DHA in triacylglycerols
was also correlated to placental FAT and FABPpm although this
association was less pronounced [20]. No corresponding significant
correlations were observed for AA. Most important for placental
transfer to the foetus seems the observation that the DHA
percentage in cord blood phospholipids showed a weak, but
significant correlation with the m-RNA expression for FATP-4 in the
placenta [18]. Although these correlations might not fully explain
the preferential transfer of LC-PUFA across the placenta, they
clearly demonstrate the importance of the carrier proteins.
LC-PUFA supply and outcomes
Some, but not all studies have shown that maternal intake of fish,
fish oils and n-3 LC-PUFA result in a slightly longer duration of
gestation and a somewhat higher birth weight [10]. Recently
meta-analyses of randomized controlled intervention trials were
published reviewing effects of n-3 LC-PUFA supplementation of women
with low risk and high risk pregnancies, respectively, on pregnancy
outcomes [21, 22] The results show that n-3 LC-PUFA supplementation
during pregnancy in general only to a small extent enhances
pregnancy duration, but the risk of early preterm delivery is
significantly reduced in high risk pregnancies (relative risk 0.39,
95% CI 0·18, 0·84).
While a large number of studies have evaluated the influence of
n-3 LC-PUFA supplementation on gestational length and birth weight,
only few randomized studies have examined the effects of perinatal
dietary LC-PUFA on neurodevelopment, but very recently in a large
cohort study it could be shown that, low maternal seafood (the
predominant source of n-3 LC-PUFA) intake during pregnancy was
associated with increased risk of their children at age 8 years to
be in the lowest quartile for the verbal intelligence quotient,
suboptimum outcomes for prosocial behaviour, fine motor,
communication, and social development scores [23].
Helland et al. performed a double blind randomized study with
pregnant women receiving daily from 17-19 weeks of gestation until
3 months after delivery 1g DHA provided with 10 ml cod liver oil,
or a placebo oil (corn oil). No differences were reported on EEG
scores at 3 months of age or Fagan test (as indicator of infant
cognitive function) at 6 and 9 months of age in the babies [24]. In
contrast, at the age of 4 years, children who were born to mothers
who had received n-3 LC-PUFA during pregnancy and lactation had
significantly higher IQ, as assessed with the Kaufman Assessment
Battery for children (K-ABC) intelligence test [25].
Infants whose mothers had higher levels of DHA in red blood
cells at birth showed more mature developmental profiles on
single-object attention measures and more optimal performance on
distractibility assessments during the 2 years of life [26].
The current results show associations between early DHA status
and cognitive function in infancy and early childhood. The
participants of an expert workshop on dietary fat intake during the
perinatal period held with support of the European Commission
recommended that pregnant and lactating women should aim to
achieving a dietary intake of n-3 LC-PUFA that supplies a DHA
intake of at least 200 mg per day. Intakes up to 1 g/day of DHA or
2.7 g/day of n-3 LC-PUFA have been used in randomized trials
without occurrence of significant adverse effects [27]. Women of
childbearing age can meet the recommended intake of DHA by
consuming one to two portions of sea fish per week, including fatty
fish which is a good source of n-3 LC-PUFA. This intake of fatty
fish rarely exceeds the tolerable intake of environmental
contaminants. Furthermore, the worhshop participants found no
evidence that women of childbearing age whose dietary intake of
linoleic acid is adequate need an additional dietary intake of
AA.
Conclusions
Fish oil supplementation during pregnancy slightly increases infant
size at birth and significantly reduces early preterm birth before
34 weeks of gestation. Several studies have provided evidence for a
link between early DHA status in the mother and cognitive
development of her child. Given the great importance of these
findings, further studies need to be performed to fully appreciate
the effects and n-3 fatty acid interventions in pregnancy, Such
studies should also aim at a further elucidation of the active and
preferential materno-fetal transfer of DHA across the placenta,
apparently mediated by specific binding and transfer proteins.
Acknowledgements
The work reported herein has been carried out with partial
financial support from the Commission of the European Communities,
specific RTD Programme “Quality of Life and Management of Living
Resources”, within the 5th. Framework Programme,
research grants no. QLRT-2001-00389 and QLK1-CT-2002-30582, and the
6th. Framework Programme, contract no. 007036 “The early
nutrition programming project”, (www.metabolic-programming.org).
This manuscript does not necessarily reflect the views of the
Commission and in no way anticipates the future policy in this
area. BK is the recipient of a Freedom to Discover Award of the
Bristol Myers Squibb Foundation, New York, NY, USA.
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