Focus Article

Altered development and function

of the placental regions in
preeclampsia and its association
with long-chain polyunsaturated
fatty acids
Alka Rani, Nisha Wadhwani, Preeti Chavan-Gautam and Sadhana Joshi*

The placenta is an essential organ formed during pregnancy that mainly trans-
fers nutrients from the mother to the fetus. Nutrients taken up by the placenta
are required for its own growth and development and to optimize fetal growth.
Hence, placental function is an important determinant of pregnancy outcome.
Among various nutrients, fatty acids, especially long-chain polyunsaturated fatty
acids (LCPUFAs), including omega 3 and omega 6 fatty acids, are essential for
placental development from the time of implantation. Studies have associated
these LCPUFAs with placental development through their roles in regulating
oxidative stress, angiogenesis, and inflammation, which may in turn influence
their transfer to the fetus. The placenta has a heterogeneous morphology with
variable regional vasculature, oxidative stress, and LCPUFA levels in healthy
pregnancies depending upon the location within the placenta. However, these
regional structural and functional parameters are found to be disturbed in
pathological conditions, such as preeclampsia (PE), thereby affecting pregnancy
outcome. Hence, the alterations in LCPUFA metabolism and transport in differ-
ent regions of the PE placenta as compared with normal placenta could poten-
tially be contributing to the pathological features of PE. The regional variations
in development and function of the placenta and its possible association
with placental LCPUFA metabolism and transport in normal and PE pregnancies
are discussed in this review. © 2016 Wiley Periodicals, Inc.
How to cite this article:
WIREs Dev Biol 2016. doi: 10.1002/wdev.238

INTRODUCTION is an important determinant of pregnancy outcome.1

T he placenta is a temporary organ formed during
pregnancy, one of its major functions being the
transfer of nutrients from the mother to the fetus for
fetal growth and development. Hence, the proper
development and efficient functioning of the placenta
*Correspondence to: srjoshi62@gmail.com
Department of Nutritional Medicine, Interactive Research School
for Health Affairs, Bharati Vidyapeeth University, Pune, India
Conflict of interest: The authors have declared no conflicts of inter-
est for this article.
Furthermore, abnormal placental development has
been shown to be associated with pregnancy disor-
ders like preeclampsia (PE).2
The placenta has specific mechanisms to main-
tain its own development and function, and to main-
tain a stable environment for fetal growth and
development.3 Nutrients taken up by the placenta
from the maternal circulation are also retained for its
own metabolism.4 Among various nutrients, fatty
acids, especially long-chain polyunsaturated fatty
acids (LCPUFAs), are one of the most important
nutrients required by the placenta from the time of

© 2016 Wiley Periodicals, Inc.

 Focus Article wires.wiley.com/devbio

implantation. LCPUFAs of the omega 3 series,
mainly docosahexaenoic acid (DHA; 22:6 n-3), and
omega 6 series, mainly arachidonic acid (AA; 20:4 n-
6), are important for placental development and as
well as being critical building blocks of fetal brain,
retina, and other neural tissues.5 We have previously
reported lower proportions of AA and DHA in
maternal plasma during the 16th–20th weeks of ges-
tation in pregnancies that progressed to PE as com-
pared with normotensive pregnancies. Furthermore,
the maternal DHA and AA levels at this time point
were positively associated with their levels in the pla-
centa and cord blood.6 We and others have demon-
strated lower DHA and total omega 3 fatty acid
levels in the PE placenta as compared with normoten-
sive placenta.6–8
The placenta has a heterogeneous structure
with the maternal basal tissue on one side and fetal
chorionic tissue on the other. It comprises several
lobules that act as independent functional units.
These lobules vary in size depending on their posi-
tion, with larger ones at the center (Figure 1).9 This
gives the placenta a unique architecture, but its
regional functionality is not well understood.
Recently, we have reported alterations in LCPUFA
levels in different regions (maternal to fetal and cen-
ter to periphery) of the PE placenta as compared with
placenta from normotensive pregnancies.10 It is likely
that the regional variations in development and func-
tion of the placenta in PE may be a result of altered
maternal LCPUFA intakes and/or metabolism
because LCPUFAs are required for placental
development.
Here we have reviewed literature on the
regional variations in development and function of
the placenta and its possible association with placen-
tal LCPUFA metabolism and transport in normal
and PE pregnancies.
FATTY ACID METABOLISM
AND TRANSPORT IN THE PLACENTA
Fatty Acid Metabolism
The placenta requires an abundant and constant
source of energy for its own rapid growth and matura-
tion where fatty acids are required as a metabolic
fuel.11 LCPUFAs are obligatory constituents of biolog-
ical membranes that maintain membrane fluidity
and intercellular signaling.12 LCPUFAs also regulate

Maternal spiral artery

Peripheral
Maternal vein region

Basal plate

Mid-disc
Uterine Amniotic region
wall cavity
Materal side

Central
Fetal side

Umbilical
region
cord
Lobule

Fetal vein

Fetal artery

Intervillous space
Chorionic plate
Villous tree

Syncytiotrophoblast layer

F I G U R E 1 | Basic structure of the placenta showing maternal and fetal sides and central, mid-disc and peripheral regions based on the cord
insertion site.

© 2016 Wiley Periodicals, Inc.

 WIREs Developmental Biology
inflammation by producing eicosanoids, protectins
and resolvins.13 Furthermore, biosynthesis of DHA
and AA occurs from its precursor alpha-linolenic acid
(ALA, 18:2), an omega 3 fatty acid and linoleic acid
(LA, 18:2) respectively via the fatty acid desaturase 1 -
(FADS1; formerly known as Δ5 desaturase), FADS2
(formerly known as Δ6 desaturase), and elongase
enzymes. The studies on the FADS enzymes in the
placenta are controversial where few reports indicate
its presence6,14,15 while others report absence of its
activity in the placenta.16–18 In the PE placenta, we
have reported reduced expression of FADS1 placenta
as compared with control placenta which would be
expected to limit the biosynthesis of AA and DHA in
the PE placenta.19
Fatty Acid Transport
The insolubility of LCPUFAs in the cytosol means
that several membrane and cytoplasmic proteins are
required for its transport including fatty acid translo-
cases (CD36/FAT), isoforms of fatty acid binding
proteins (FABPs), fatty acid transport proteins
(FATPs), and long-chain acyl coenzyme-A synthe-
tases (ACSLs).20,21 In the placenta, fatty acids pass
through the villous syncytiotrophoblast layer, which
is of around 4 mm thickness and consists of a micro-
villus membrane facing toward the maternal circula-
tion and basal membrane facing toward the fetal
circulation. FATPs and FAT/CD36 are proteins
located on both the microvillus and basal membranes
for transmembrane transport, while FABPs function
as intracellular trafficking protein.22,23 A plasma
membrane fatty acid binding protein (p-FABPpm)
has also been identified in the placenta exclusively
present on the microvillus membrane.24 (Figure 2)
ACSL6 has been found to function primarily in DHA
metabolism, and its overexpression increases incor-
poration of AA and DHA into phospholipid and tri-
glycerides.25 Mouse mutagenic studies have shown
that accumulation of LA and ALA are significantly
reduced in FABP3-knockdown mice compared with
controls.26 The placental expression of FATP-1 and
FATP-4 genes has been shown to be positively corre-
lated with the preferential incorporation of maternal
eicosapentaenoic acid (EPA; 20:5 n-3) and DHA in
placental phospholipids, which could be the mechan-
ism of selective transfer of these fatty acids to the
fetus in healthy pregnancies.27 We have observed
reduced mRNA expression of FATP1 and FATP4 in
PE placenta as compared with the normotensive con-
trol which may affect the transfer of fatty acids to
the fetus.6 However, another study has reported ele-
vated levels of FATP4 and but no change in the
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
mRNA levels in PE placenta as compared with con-
trol.28 These studies are of significance because
LCPUFA taken up by the placenta is critical for its
own as well as fetal development which is compro-
mised in PE.
Regulation of Fatty acid Metabolism
and Transport
There are a number of nuclear transcription factors
that have been identified in the placenta including
peroxisome proliferator-activated receptors (PPARs),
sterol regulatory element-binding proteins (SREBPs),
liver X receptors (LXRs), and retinoid X receptors
(RXRs). These receptors are activated by ligand-
dependent or -independent pathways to promote the
transcription of genes involved in development and
function of the placenta.29 LCPUFAs and its metabo-
lites activate PPARs, which forms heterodimers with
other transcription factors like like PPAR/RXR and
PPAR/LXR to regulate the expression of genes
involved in placental development as well as fatty
acid metabolism and transport.30 PPAR regulates
fatty acid beta-oxidation and the expression of
FATP1 and FATP4 in human trophoblast cells.
However, FADS1 and FADS2 expression is regulated
by SREBP-1C and PPARA (formally known as
PPAR-alpha) transcription factors.31,32 Intrauterine
growth restriction (IUGR) in PE has been found to
be associated with higher PPARG (formally known
as PPAR-gamma) DNA binding capacity as com-
pared with control suggesting the involvement of
PPARs in the pathophysiology of PE.19 In a rat
model, PPARG antagonist treatment has been shown
to induce endothelial dysfunction and increase solu-
ble fms-like tyrosine kinase 1 (sFLT1), a potent bio-
marker of PE.33
REGIONAL DEVELOPMENT
AND FUNCTION OF THE PLACENTA:
POSSIBLE ROLE OF LCPUFAS
Implantation
During implantation, fatty acids are required for
structural and functional growth of the embryo at
the implantation site.34 From implantation, until the
onset of maternal blood flow in the placenta, the con-
ceptus is supported by the secretions from the endo-
metrial gland delivered into the placenta. This
secretion contains numerous lipid droplets which reg-
ulate placental cell proliferation and differentiation
in the early stages of the pregnancy.35 However, the
type of fatty acids present in the endometrial
 Focus Article wires.wiley.com/devbio

Intervillous space
NEFA
1
p-FABPpm
3
2

MVM

FATP

5
4

ACSL

ER
Lipid droplet PL
Cytosol

Syncytiotrophoblast
13

12 7
14
FADS
FA-CoA PPAR/RXR
11 FABP 16

15 DNA
Mitochondria 8 16
Nucleus
9
10
PGs
BM

FAT/CD36

Cytotrophoblast

Fetal
capillary
Fibroblast

F I G U R E 2 | Metabolic pathways of fatty acids in syncytiotrophoblast layer of the placenta. (1, 2, & 3) NEFA are up taken by FATP, FAT/CD36)
and p-FABPpm from maternal circulation in the IVS or (4) get directly diffused through plasma membrane. (5) Up taken fatty acids get activated by
ACSL to form fatty acid acyl-CoA or (6) bind to FABP which is (7) interconvertable. Fatty acids take various pathways based on the requirement
which includes (8, 9, & 10) transport to the fetal circulation, (11) mitochondrial β-oxidation, (12) storage in the form of lipid droplets,
(13) incorporation in PL of plasma membrane, (14) synthesis of LCPUFA with the help of FADS, (15) formation of active metabolites. (16) Fatty
acids and its metabolites are ligands of transcription factors like PPAR which then forms heterodimer with RXR to initiate transcription of genes.
NEFA, nonesterified fatty acid; IVS, intervillous space; MVM, microvillus membrane; BM, basal membrane; PL, phospholipids; PGs, prostaglandins;
LCPUFA, long-chain polyunsaturated fatty acid; ER, endoplasmic reticulum; PPAR, peroxisome proliferators-activated receptor; RXR, retinoid X
receptor; FABP, fatty acid binding protein; p-FABPpm, placenta-specific plasma membrane; FABP, FAT/CD36, fatty acid translocase; FATP, fatty acid
transport protein; ACSL, acyl co-A synthetase; FADS, fatty acid desaturase.

secretion is not well characterized. Studies indicate
that, along with other fatty acids, human embryos
have a high requirement for unsaturated fatty acids,
particularly in the later stages of preimplantation.36
Furthermore, prostaglandins derived from AA have
been reported to play an indispensable role in
increasing the vascular permeability, trophoblast
invasion, and extracellular matrix remodeling during
implantation mediated via PPARD (formally known
as PPAR-delta).37,38 PPARG and PPARB (formally
known as PPAR-beta) knockout mice are associated
with embryonic-lethality due to defects in placental
morphogenesis while PPARA knockout mice are
associated with increased rates of maternal abor-
tion.39 These studies suggest a need for LCPUFA
from the time of implantation for the development of
embryo and the placenta.
First Trimester
After implantation, the fetal chorionic plate starts
proliferating toward the maternal uterine wall.

© 2016 Wiley Periodicals, Inc.

 WIREs Developmental Biology
Placental trophoblasts migrate toward the decidua,
remodel and form a vascular network with the
maternal spiral arteries (Figure 3).40 The spiral
arteries undergo these physiological changes first at
the center and later extend centrifugally in annular
manner toward the periphery. There is a differential
cell maturity, invasion, and plugging of endometrial
arteries in the peripheral and the central regions of
the placenta where the youngest dividing cells are at
the center of the disk.41 Furthermore, the process of
arterial vessel networking in the placenta involves
angiogenesis and vascularization which require sev-
eral growth factors, including vascular endothelial
growth factor (VEGF).42
Trophoblast cells majorly express angiogenic
factors to promote placental vascularization process;
however, the angiogenesis is also influenced by other
factors present in the cells. Reports from cell culture
studies indicate that various LCPUFAs and their deri-
vatives when supplemented in culture media have
shown to promote the pro-angiogenic activities of the
first trimester trophoblast cells. One study reported
that DHA stimulates the expression of VEGF while
EPA and AA stimulate other weaker angiogenic fac-
tors like angiopoietin-like 4 (ANGPTL4).43 Prosta-
glandins PGE-2 synthesized from AA are involved in
angiogenesis by stimulating fibroblast growth factor
receptor 1.44 Furthermore, dietary fatty acids like cis-
9,trans-11 conjugated linoleic acid (c9t11 CLA; 18:2
n-6), EPA, and DHA stimulate the expression of
FABP4 (>twofolds) which is also reported to directly
modulate angiogenesis as well as lipid metabolism in
the placenta.45 Thus, angiogenesis is crucial for pla-
cental development in this trimester during which
LCPUFAs have been found to play a stimulatory
role. There are regional differences in the degree of
vascularization in the placenta which may be associ-
ated with variations in LCPUFA metabolism across
the placenta.
Second Trimester
At the beginning of the second trimester, invasion of
trophoblasts is progressively completed. The unplug-
ging of spiral arteries and onset of maternal blood
flow is initiated in the periphery of the placenta and
expands progressively to the remainder of the placen-
tal bed (Figure 3(e)). Impedance of blood flow
through spiral arteries has been found to be lower in
the central area of the placental bed.46 This onset of
blood flow rapidly increases the oxygen tension by
threefold in the intervillous space. It has been sug-
gested that a sudden increase in oxidative stress is
required to switch the proliferative phenotype of
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
cytotrophoblasts to an invasive one.47 Excessive oxi-
dative stress due to free radicals needs to be con-
trolled by the antioxidant defence mechanism.
Hence, there can be variable oxidative stress expo-
sure of the trophoblasts depending upon their loca-
tion within the placenta, the availability of
antioxidant machinery and the stage of development.
The oxidative stress in the placenta has exten-
sively been linked with unsaturated fatty acids. Stud-
ies on placental BeWo cell lines, explants, and rats
indicate that at lower doses, omega 3 fatty acid (espe-
cially DHA) reduces placental oxidative stress and
oxidative DNA damage and increases the levels of
resolvins, protectins, and total antioxidant
capacity.48–51 However, in contrast, free radicals are
also known to peroxidize LCPUFA, which is injuri-
ous to the cells.52 A recent human study reported
that diets rich in EPA and DHA during pregnancy
were unable to reduce inflammatory cytokine levels
in the placenta.53 However, in another study, individ-
ual supplementation of oleic acid (OA; 18:1), DHA
and EPA to placental explant culture media was able
to reduce the production of interleukin6 (IL6) while
combination of these fatty acids was found to have
no effect on the inflammatory cytokine levels.54 A
supplementation study in sheep showed that LA inhi-
bits both prostaglandin1 (PGE1) and PGE2 produc-
tion while AA stimulates PGE1 and PGE2
production in the placenta.55 Thus, these studies sug-
gest that the effect of LCPUFA supplementation may
vary depending on the dose and combination of the
LCPUFA, presence of antioxidants, developmental
stage, and experimental system. It is therefore likely
that the LCPUFA metabolism will vary within the
placental bed based on the extent of oxidative stress
and inflammation in different regions of the placenta.
Third Trimester
The placenta becomes stabilized with optimum activ-
ity of antioxidant enzymes and fully developed vil-
lous trees by the third trimester. Before the start of
this trimester, the blood flow inside the placenta
structurally remodels it to form lobular compart-
ments (Figure 3(f )).56 Maternal blood delivered into
the middle of a lobule percolates and drains into the
uterine veins for the efficient exchange of oxygen and
nutrients. It has been suggested that an oxygen gradi-
ent most likely exists from the center to the periphery
and maternal to the fetal side of each lobule.57
During the third trimester, the fatty acid
requirement of the fetus increases exponentially.
There is a preferential transfer of DHA and AA
through the placenta and higher incorporation of
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(a) Uterine vein (b) (c)

Uterine artery
Radial vein
Radial artery
Young proliferating
Spiral artery trophoblasts
(centre) Intervillous space
Endometrium
(Uterine wall)

Endometrial vein

Endometrial artery Extending blood

Syncytiotrophoblast vessel
Amniotic cavity Matured trophoblasts
Embryonic disc (periphery)
Cytotrophoblast
Endometrial epithelium

(Week 1) (Week 2) (Week 3)

(d) (e)
Decidua basalis
Extravillous trophoblast

Onset of blood
Plugging of flow
spiral artery
Chorionic frondosum Umbilical vein
Allantois
Umbilical artery
Yolk sac
Amnion
Chorionic cavity
Chorionic laeve

Decidua capsularis

(4–7 Weeks) (8–14 Weeks)

(f) (g)

Basal plate

Placenta
Villous tree

Cord
Syncytiotrophoblast
layer
Cytotrophoblast Amniotic cavity
layer
Lobule

Lacuna (Intervillous
space with blood)
Umbilical cord
Fetus
Fetus

Amnion
Chorion

Uterus

(16–20 Weeks) (20 Weeks onwards)

F I G U R E 3 | Development of the placenta across gestation. (a) Rapidly proliferating young placental trophoblast cells at the site of
implantation in the endometrium of the uterus; (b) matured syncytiotrophoblast cells propagate toward the periphery increasing the surface area
of the placenta; (c) formation of intervillous space and extension of maternal blood vessels toward the developing placenta; (d) remodeling of
terminal spiral arteries and plugging the inlet with cytotrophoblast cells to restrict the entry of maternal blood inside the developing placenta;
(e) unplugging of spiral arteries inlet and onset of maternal blood flow in the placenta starting from periphery and progressing toward the center;
(f ) complete establishment of blood flow in the placenta leading to the formation of villous tree lobules; (g) fully developed placenta to accelerate
the process of nutrient transfer from maternal to the fetal circulation.

© 2016 Wiley Periodicals, Inc.

 WIREs Developmental Biology
DHA and AA has been reported in the phospholipids
in placental BeWo cell line studies.58 Stable isotope
studies have shown higher ratio of DHA in cord
blood as compared with maternal circulation than
other LCPUFAs during third trimester of the preg-
nancy. FATP-1, FATP-4, and p FABPpm are directly
involved in the uptake of DHA from the maternal
circulation. Furthermore, FABP1 and FABP3 have
highest binding affinity for DHA and AA to trans-
port it toward the fetal circulation.20,59 In conditions
of increased cellular fatty acid metabolism, these pro-
teins are upregulated and facilitate transfer across
membranes and intracellular channeling of fatty
acids.60 This has implications for preferential transfer
of AA and DHA for optimal development of fetal
brain, retina, and neurons in the third trimester. The
transfer of fatty acid through the placenta is driven
by its concentration gradient between the mother
and the fetus.3 The concentration gradient within
the placenta may require differential expression of
the transport and binding proteins to accelerate the
transfer toward the fetus.
Numerous processes in placental development
and function are associated with LCPUFAs right
from implantation.
REGIONAL DIFFERENCES IN
NORMAL AND PE PLACENTA
Normal Placenta
Early gestational events like differential trophoblast
cell growth and onset of maternal blood are the two
main phenomena which lead to the regional bifurca-
tions across the placenta in normal pregnancies.61 A
number of studies have reported morphological and
developmental bifurcations in various regions of the
placenta.61–65 Amongst these, few studies have con-
sidered cord insertion as the center while others have
considered the geometric center of the placental
disk.64,66–68 However, on an average 75% of the
cord insertions are found to be in the central region
of the placenta.69 Noncentral cord insertion in the
placenta has been reported to reduce the transport
efficiency and chorionic vascular distribution leading
to reduced birth weight.70
Table 1 shows the list of studies in the placenta
which have examined region-wise changes. The
expression of hypoxia related growth factors like
VEGF and connective tissue growth factor (CTGF)
was found to be reduced near the cord insertion indi-
cating oxygen gradient within the normal placenta
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
based on cord insertion.64 There are other studies
where oxidative stress markers such as MDA and
SOD have been found to vary within the placental
bed.74 In spite of the different sampling methods used
in these studies (Table 1), most studies indicate that
there are regional differences in gene expression
and/or protein levels of various enzymes, nutrients,
and their transporters within a normal placenta. This
indicates that the development and function of the
placenta is not uniform and that there are regional
variations from the maternal to the fetal side and
from the center to the periphery.
Regional fatty acid metabolism and transport
are the most understudied area of placental biology.
There are some studies which have reported hetero-
geneity in the fatty acid content of the placenta based
on the location of the sampled tissue.78,79 In our
recent study, we have observed higher AA in fetal
side than the maternal side around the cord insertion
in the normal term placenta which may be due to
preferential transfer of AA from mother to the
fetus.10 However, another study on normal term pla-
centa showed no difference in the expression of
FATP1, FATP4, and FABP3 in different placental
regions including center (cord insertion), periphery,
basal plate, and chorionic plate.77 These are very lim-
ited regional studies and there are no studies at dif-
ferent gestation time points to evidently understand
the link between LCPUFA metabolism and placental
development.
PE Placenta
Disturbances in the early developmental processes of
the placenta result in the manifestation of PE.80
These processes include premature entry of maternal
blood in the central region of the placenta, increasing
the oxidative stress and derailing the remodeling
process of the spiral arteries.81,82 In later stages, the
velocity of blood through these constricted spiral
arteries ruptures the anchoring villi and shortens the
time of oxygen and nutrient exchange in the PE pla-
centa.83 As a result of the damage, placental villous
fragments are released into the maternal circulation,
leading to clinical symptoms like hypertension and
proteinuria of PE in the mothers.2
There are many studies which show disturbed
regional placental development and metabolism in
pathological conditions and are shown in Table 2.
Studies on expression of antioxidant enzymes
showed reduced placental glutathione peroxidase
(GPX) in PE as compared with control and this dif-
ference was more pronounced near the site of cord
insertion.87,88 Recent studies from our group have
 TABLE 1 | Studies on Regional Variations in the Placenta from Normal Pregnancies
Focus Article

Sampling Regional
Groups Regions Taken Criteria Parameters Studied Summary Variation References
Term NC (n = 147) Peri-insertion, mid-disc (maternal Cord insertion Levels of zinc, iron, copper, and Calcium highest in periphery, iron Yes 71

and fetal halves), periphery as center calcium highest in peri-insertion, zinc

lowest in fetal mid-disc
Term NC (n = 31) Peri-insertion, mid-disc (maternal Cord insertion Levels of SOD, catalase, GPX, GPX lower in periphery than peri- Yes 72

and fetal halves), periphery as center glutathione transferase, insertion

glutathione reductase, and
glucose-6-phosphate
dehydrogenase
Second trimester NC (n = 64) Central and periphery Cord insertion Color Doppler of spiral arterial Lower impedance of blood flow Yes 46

as center blood flow in center

Vaginal term NC (n = 6) 9 sites from center to the lateral Cord insertion Gene expression of VEGF, CTGF, Lower expression of hypoxia Yes 64

border and the basal to the as center NDRG1, LAMA3, RAD, alpha- related transcripts in proximity
chorionic plate tubulin, and adipophilin to the cord insertion
Vaginal term NC (n = 8) Chorionic plate, stem villi and Regions from Immunohistochemistry and Higher expression of MMP3 and Yes 73

basal plate one lobule zymography of MMP2, MMP3, MMP9 in the basal plate
and MMP9
Vaginal term NC (n = 45) Central, mid-placenta and Cord insertion Levels of MDA and SOD MDA highest in fetal mid- Yes 74

periphery from maternal and as center placenta and SOD highest in

© 2016 Wiley Periodicals, Inc.

fetal sides fetal central side
Vaginal term NC (n = 12) 9 sites from center to periphery Cord insertion Levels of ACE ACE activity increasing to the Yes 65

as center periphery
Labor vaginal and nonlabor Inner, middle and outer zones Cord insertion Protein and gene expression of Lower HSP27 in inner zone in Yes 75

cesarean term NC (n = 6) as center HSP27 both labor and nonlabor

groups
Labor vaginal and nonlabor Inner, middle and outer zones Cord insertion Protein and gene expression of No difference in any of the No 76

cesarean term NC (n = 6) as center PON2 groups

Nonlabor cesarean term NC Chorionic plate, basal plate, Cord insertion Gene expression of FATP1, No differences within the regions No 77

(n = 5) central villi and peripheral villi as center FA0054P4, FABP1, and FABP3
NC, normotensive control; SOD, superoxide dismutase; GPX , glutathione peroxidize; VEGF, vascular endothelial growth factor; CTGF, connective tissue growth factor; NDRG1, N-myc downstream-regulated
gene 1; LAMA3, laminin alpha 3; RAD, ras-associated with diabetes; MMP, matrix metalloproteinase; MDA, malondialdehyde; ACE, angiotensin-converting enzyme; HSP, heat-shock protein; PON2,
paraoxonases-2; FATP, fatty acid transport protein; FABP, fatty acid binding protein.
wires.wiley.com/devbio
 TABLE 2 | Studies on Regional Variations in the Placenta from Complicated Pregnancies
Summary
Sampling Parameters Regional
Groups Regions Criteria Studied Within groups Between groups Alteration References
NC (n = 7) and PE (n = 10) Center and Cord insertion Extracellular SOD No difference from center to No alterations observed between No 84

periphery as center levels periphery in both the NC and PE

groups
Gestation 26–38 weeks of PE (n = 6) Basal plate and Geometric Gene and protein No significant differences Lower IGFBP1 mRNA in center Yes 85

and NC (n = 6) chorionic villi center expression of observed in both the and periphery of basal plate in
WIREs Developmental Biology

from center IGF II and groups PE than NC

and periphery IGFBP1
PE with gestation < 28 weeks (n = 7), Basal plate and Geometric Gene and protein No difference from center to No significant alterations No 67

PE with gestation > 28 weeks chorionic villi center expression of periphery in NC observed
(n = 15), NC with gestation from center ADM
< 28 weeks (n = 6), PE with and periphery
gestation > 28 (n = 13)
PE with gestation < 28 weeks (n = 5), Basal plate and Geometric Gene and protein No difference from center to Higher RTP mRNA in chorionic Yes 86

PE with gestation > 28 weeks chorionic villi center expression of periphery in NC villi in PE than NC
(n = 15), NC with gestation from center RTP (GA < 28 weeks)
<28 weeks (n = 6), PE with and periphery
gestation > 28 (n = 13)
Term vaginal NC (n = 12), term or Inner, middle Cord insertion Protein Intense staining for GPX3 GPX activity reduced in inner Yes 87

preterm and vaginal or cesarean PE and outer as center expression of toward the inner region in and middle regions in PE
(n = 12) regions GPX1, GPX3, NC while toward the
and GPX4 outer region for GPX4 in

© 2016 Wiley Periodicals, Inc.

PE
Term labor vaginal NC (n = 14), Peri-insertion, Cord insertion Protein and gene No effect of site distance Lower expression of SOD1 in Yes 68

nonlabor cesarean NC (n = 9), term mid-disc and as center expression of from cord nonlabor and higher SOD2
or preterm labor PE (n = 11) and periphery from SOD1, SOD2, and SOD3 in labor in both the
nonlabor PE (n = 14) villi and and SOD3 sides of PE than NC
maternal side
Term labor vaginal NC (n = 14), Peri-insertion Cord insertion Gene expression Higher GPX1 near cord GPX4 mRNA expression lower in Yes 88

nonlabor cesarean NC (n = 9), term and periphery as center of GPX1, insertion than periphery in both the regions in both
or preterm labor PE (n = 11) and GPX2, GPX3, labor in both PE and NC groups of PE than of NC, HO1
nonlabor PE (n = 14) GPX4, HSP70, lower in both the regions in
and HO1 labor in PE than NC
Term labor vaginal NC, nonlabor Inner and middle Cord insertion Protein and gene Not Analyzed Higher in middle zone in labor in Yes 89

cesarean NC, labor PE and nonlabor regions as center expression of PE than NC

PE (n = 6 each) HSP27
Altered development and function of the placental regions
 Focus Article

TABLE 2 | Continued
Summary
Sampling Parameters Regional
Groups Regions Criteria Studied Within groups Between groups Alteration References
Term labor vaginal NC, nonlabor Inner, middle Cord insertion Protein and gene Higher HSP70 in middle Higher HSP70 in inner zone in Yes 90

cesarean NC (n = 6 each), labor PE and outer as center expression of zone in labor and inner nonlabor and lower in middle
(n = 6) and nonlabor PE (n = 4) zones HSP70 and middle zones in zone in labor group in PE than
nonlabor group than NC
outer zone
Term labor vaginal NC and PE, Inner, middle, Cord insertion Protein and gene No differences Lower PON2 in middle zone in Yes 91

nonlabor cesarean NC and PE (n = 6 and outer as center expression of PE than NC in both labor and
each) zones PON2 nonlabor groups
Term or preterm, vaginal or cesarean, Proximal, Cord insertion Gene expression Highest IGFBP1 and lowest IGFBP1, prolactin, CRH and Yes 92

IUGR (n = 22) and AGA (n = 19) intermediate as center of IGFBP1, leptin in proximal region leptin higher in intermediate
and periphery prolactin, CRH, in IUGR region in IUGR than NC
and leptin
Term PE (n = 21), preterm PE (n = 26) Fetal and Cord insertion Levels of NGF BDNF highest in central fetal NGF higher in all the regions Yes 93

and NC (n = 50) maternal from as center and BDNF in NC except central fetal in preterm
center and PE than NC
periphery
Term PE (n = 11), preterm PE (n = 14) Fetal and Cord insertion Levels of MDA, Higher MDA in central MDA lower in all the regions of Yes 94

© 2016 Wiley Periodicals, Inc.

and NC (n = 35) maternal from as center GPX, and maternal than fetal in NC than both the PE groups
center and catalase preterm PE and GPX and GPX lower in periphery in
periphery higher in peripheral preterm PE than NC
maternal than central
fetal in NC
Term PE (n = 20), preterm PE (n = 24) Fetal and Cord insertion Fatty acid levels Higher AA in central fetal DHA lower in center in preterm Yes 10

and NC (n = 69) maternal from as center than central maternal in PE than NC

center and NC and DHA higher
periphery toward periphery than
center in preterm PE
NC, normotensive control; PE, preeclampsia; IUGR, intrauterine growth restriction; AGA, appropriate for gestational age; SOD, superoxide dismutase; GPX, glutathione peroxidize; HSP, heat-shock protein; IGF
II, insulin-like growth factor II; PON2, paraoxonases-2; IGFBP1, insulin-like growth factor-binding protein 1; ADM, adrenomedullin; RTP, tunicamycin-responsive protein; HO1, heme-oxygenase 1; CRH, cortico-
tropin releasing hormone; NGF, nerve growth factor; BDNF, brain-derived nerve growth factor; MDA, malondialdehyde; AA, arachidonic acid; DHA, docosahexaenoic acid.
wires.wiley.com/devbio
 WIREs Developmental Biology
shown differential regional levels of malondialdehyde
(MDA), GPX, and neurotrophins in PE placenta
where GPX was observed to be lower in the periph-
eral regions of the preterm PE placenta as compared
with control. Furthermore, in the central part of the
preterm PE placenta MDA was observed to be higher
in basal plate as compared with chorionic
plate.85,93–95 There was decreased insulin-like growth
factor binding protein 1 (IGFBP1) mRNA expression
in basal plate decidua in PE placenta as compared
with control, indicating nondecidual origin of
IGFBP1.85 It is therefore likely that disturbed growth
and oxygenation within the PE placenta may affect
its regional development due to altered expression of
critical regulatory genes.
Recently, for the first time, we have reported
regional variation in fatty acid levels in the PE pla-
centa as compared with the normotensive control
placenta.10 The levels of AA were found to be
higher in the fetal side than the maternal side of the
normotensive placenta which could be due to prefer-
ential transport and higher incorporation of AA in
the membrane phospholipids toward the fetal side
of the placenta. Such a gradient was not observed in
the regions of PE placenta. In this study, we also
Altered FA
metabolism/ intake
Al
te
re
d
LC
PU
Mother
Placenta
Adult
Risk of Fetus
non communicable LC
e d
diseases t er
Al
Fetal growth
restriction
FI GU RE 4 | Overview of proposed altered regional fatty acid metabolism and transfer in preeclampsia placenta. In preeclampsia, the disturbed
maternal LCPUFA supply to the placenta alters its regional development. This affects LCPUFA transfer to the fetus which hampers intrauterine fetal
growth and increases the risk of noncommunicable diseases in the adult life.
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
observed lower DHA and total omega 3 fatty acid
levels in the center (with respect to the cord inser-
tion) than the periphery (farthest from the cord
insertion) of the preterm PE placenta. When the
fatty acid levels in different regions were compared
between groups, we observed higher levels of ALA
but lower levels of DHA in central fetal region of
the preterm PE placenta which may indicate lower
substrate to product conversion in this region. DHA
and total omega 3 fatty acid levels were found
lower in the center of the preterm PE as compared
with term PE and normotensive placenta. Previous
studies have shown that the maternal blood enters
early in the central region of the placenta thereby
affecting the development of young dividing tropho-
blasts in abnormal pregnancies such as miscarriage
and PE.61,96 It is therefore likely that the center of
the placenta is more affected early in pregnancy
thereby affecting the fatty acid transport and the
metabolism in this region. Furthermore, in the fetal
side of the placenta, DHA levels in the periphery
were found to be positively associated with birth
weights in the PE group but not in the control
group. Studies need to be undertaken to examine
whether the changes in fatty acid levels are
Regional differences
in invasion, blood flow, &
oxygen concentration Insufficient trophoblast
Pathology
invasion
FA
Incomplete spiral arteries
remodeling
Placental
Altered regional
LCPUFA transport & Early onset of maternal
metabolism blood flow
Premature exposure to
Preeclampsia
F A oxidative stress
PU
Disturbed morphology and
Regional differences development
in antioxidants, growth
factors & transporters
 Focus Article
associated with alterations in fatty acid transport
and metabolism in the PE placenta.
Differential trophoblast cell growth and onset of
maternal blood are the two main phenomena
which lead to the regional bifurcations across
the placenta.
DISCUSSION AND CONCLUSION
As reviewed above, numerous processes in placental
development and function are associated with LCPU-
FAs beginning from implantation. There exists a dif-
ferential regional vasculature and oxygen tension
within the placenta which is further altered in
PE. This may be associated with altered fatty acid
metabolism and transport in various regions of pla-
centa (Figure 4). This is supported by our very recent
study which shows differential regional fatty acid dis-
tribution in control and PE placenta. Future studies
on LCPUFA transport proteins and biosynthesizing
enzymes will help us to understand the observed
regional differences in control and PE placenta.
FURTHER READING
Benirschke K, Burton GJ, Baergen RN. Pathology of the Human Placenta. New York: Springer; 2012.
REFERENCES
1. Desforges M, Sibley CP. Placental nutrient supply and
fetal growth. Int J Dev Biol 2010, 54:377–390.
doi:10.1387/ijdb.082765md.
2. Roberts JM, Escudero C. The placenta in preeclamp-
sia. Pregnancy Hypertens 2012, 2:72–83. doi:10.1016/
j.preghy.2012.01.001.
3. Brett KE, Ferraro ZM, Yockell-Lelievre J, Gruslin A,
Adamo KB. Maternal–fetal nutrient transport in preg-
nancy pathologies: The role of the placenta. Int J Mol Sci
2014, 15:16153–16185. doi:10.3390/ijms150916153.
4. Herrera E. Implications of dietary fatty acids during
pregnancy on placental, fetal and postnatal
development—a review. Placenta 2002, 23(suppl A):
S9–S19. doi:10.1053/plac.2002.0771.
5. Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE.
Essential fatty acids in visual and brain development.
Lipids 2001, 36:885–895. doi:10.1007/s11745-001-
0798-1.
6. Wadhwani N, Patil V, Pisal H, Joshi A, Mehendale S,
Gupte S, Wagh G, Joshi S. Altered maternal
© 2016 Wiley Periodicals, Inc.
wires.wiley.com/devbio
However, this study was on placenta collected after
delivery and hence the scenario during early placental
development cannot be predicted and more studies
are required on the early placenta.
The placenta has the ability to protect the fetus
from adverse genetic and environmental conditions
through plasticity in gene expression achieved by epi-
genetic processes. Furthermore, genetic and epigenetic
studies have shown considerable variations within
and between placentas that can be attributed to intra-
uterine environmental factors such as nutrition and
oxygen exposure.97 Recent studies indicate that nutri-
ents including fatty acids can interact and modify the
placental epigenome.98 Therefore, it is likely that
region wise alterations in the fatty acid transport and
metabolism may be associated with variations in pla-
cental epigenetic patterns having implications for pla-
cental function and hence birth outcome and fetal
programming of adult diseases. Thus, there is a need
for extensive research to understand the regional het-
erogeneity of the placenta, the mechanisms behind
regional variations in nutrient transport across the
placenta particularly in pathological conditions and
their implications for fetal growth and development.
proportions of long chain polyunsaturated fatty acids
and their transport leads to disturbed fetal stores in pre-
eclampsia. Prostaglandins Leukot Essent Fatty Acids
2014, 91:21–30. doi:10.1016/j.plefa.2014.05.006.
7. Wang Y, Walsh SW, Kay HH. Placental tissue levels of
nonesterified polyunsaturated fatty acids in normal
and preeclamptic pregnancies. Hypertens Pregnancy
2005, 24:235–245. doi:10.1080/10641950500281118.
8. Kulkarni AV, Mehendale SS, Yadav HR, Joshi SR.
Reduced placental docosahexaenoic acid levels associ-
ated with increased levels of sFlt-1 in preeclampsia.
Prostaglandins Leukot Essent Fatty Acids 2011,
84:51–55. doi:10.1016/j.plefa.2010.09.005.
9. Hempstock J, Bao YP, Bar-Issac M, Segaren N,
Watson AL, Charnock-Jones DS, Jauniaux E,
Burton GJ. Intralobular differences in antioxidant
enzyme expression and activity reflect the pattern of
maternal arterial bloodflow within the human pla-
centa. Placenta 2003, 24:517–523. doi:10.1053/
plac.2002.0955.
 WIREs Developmental Biology
10. Rani A, Chavan-Gautam P, Mehendale S, Wagh G,
Joshi S. Differential regional fatty acid distribution in
normotensive and preeclampsia placenta. BBA Clin
2015, 4:21–26. doi:10.1016/j.bbacli.2015.06.004.
11. Rakheja D, Bennett MJ, Foster BM, Domiati-Saad R,
Rogers BB. Evidence for fatty acid oxidation in human
placenta, and the relationship of fatty acid oxidation
enzyme activities with gestational age. Placenta 2002,
23:447–450. doi:10.1053/plac.2002.0808.
12. Holman RT, Johnson SB, Ogburn PL. Deficiency of
essential fatty acids and membrane fluidity during
pregnancy and lactation. Proc Natl Acad Sci USA
1991, 88:4835–4839.
13. Calder PC. n-3 polyunsaturated fatty acids, inflamma-
tion, and inflammatory diseases. Am J Clin Nutr 2006,
83:1505S–1519S.
14. Cho HP, Nakamura M, Clarke SD. Cloning, expres-
sion, and fatty acid regulation of the human delta-5
desaturase. J Biol Chem 1999, 274:37335–37339.
doi:10.1074/jbc.274.52.37335.
15. Muth A, Mosandl A, Bursen A, Marschalek R,
Sewell AC, Bohles H. Multidimensional gas
chromatography–mass spectrometry for tracer studies
of fatty acid metabolism via stable isotopes in cultured
human trophoblast cells. J Chromatogr B Analyt Tech-
nol Biomed Life Sci 2003, 791:235–244. doi:10.1016/
S1570-0232(03)00220-4.
16. Chambaz J, Ravel D, Manier MC, Pepin D,
Mulliez N, Bereziat G. Essential fatty acids intercon-
version in the human fetal liver. Biol Neonate 1985,
47:136–140.
17. Bereziat G, Thomas G, Cardot P, Chambaz J. Essential
fatty acid interconversion during the prenatal period:
influence of dietary factors. In: Ghisolfi J, Putet G, eds.
Essential Fatty Acids and Infant Nutrition. Paris: John
Libbey; 1992, 45–55.
18. Haggarty P, Page K, Abramovich DR, Ashton J,
Brown D. Long-chain polyunsaturated fatty acid trans-
port across the perfused human placenta. Placenta
1997, 18:635–642.
19. Holdsworth-Carson S, Lim R, Mitton A,
Whitehead C, Rice G, Permezel M, Lappas M. Peroxi-
some proliferator-activated receptors are altered in
pathologies of the human placenta: gestational diabetes
mellitus, intrauterine growth restriction and pree-
clampsia. Placenta 2010, 31:222–229. doi:10.1016/j.
placenta.2009.12.009.
20. Larque E, Demmelmair H, Gil-Sanchez A, Prieto-
Sanchez MT, Blanco JE, Pagan A, Faber FL,
Zamora S, Parrilla JJ, Koletzko B. Placental transfer of
fatty acids and fetal implications. Am J Clin Nutr
2011, 94:1908S–1913S. doi:10.3945/ajcn.110.001230.
21. Cunningham P, McDermott L. Long chain PUFA
transport in human term placenta. J Nutr 2009,
139:636–639. doi:10.3945/jn.108.098608.
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
22. Storch J, Thumser AE. Tissue-specific functions in the
fatty acid-binding protein family. J Biol Chem 2010,
285:32679–32683. doi:10.1074/jbc.R110.135210.
23. Schwenk RW, Holloway GP, Luiken JJ, Bonen A,
Glatz JF. Fatty acid transport across the cell mem-
brane: regulation by fatty acid transporters. Prosta-
glandins Leukot Essent Fatty Acids 2010, 82:149–154.
doi:10.1016/j.plefa.2010.02.029.
24. Lager S, Powell TL. Regulation of nutrient transport
across the placenta. J Pregnancy 2012, 2012:179827.
doi:10.1155/2012/179827.
25. Marszalek JR, Kitidis C, DiRusso CC, Lodish HF.
Long-chain acyl-CoA synthetase 6 preferentially pro-
motes DHA metabolism. J Biol Chem 2005,
280:10817–10826. doi:10.1074/jbc.M411750200.
26. Islam A, Kagawa Y, Sharifi K, Ebrahimi M,
Miyazaki H, Yasumoto Y, Kawamura S,
Yamamoto Y, Sakaguti S, Sawada T, et al. Fatty acid
binding protein 3 is involved in n-3 and n-6 PUFA
transport in mouse trophoblasts. J Nutr 2014,
144:1509–1516. doi:10.3945/jn.114.197202.
27. Larque E, Krauss-Etschmann S, Campoy C, Hartl D,
Linde J, Klingler M, Demmelmair H, Cano A, Gil A,
Bondy B, et al. Docosahexaenoic acid supply in preg-
nancy affects placental expression of fatty acid trans-
port proteins. Am J Clin Nutr 2006, 84:853–861.
28. Yan JY, Wang XJ. [Expression and significance of adi-
pocyte fatty acid-binding protein in placenta, serum
and umbilical cord blood in preeclampsia]. Zhonghua
Fu Chan Ke Za Zhi 2010, 45:885–890.
29. Duttaroy AK. Fatty acid-activated nuclear transcrip-
tion factors and their roles in human placenta. Eur J
Lipid Sci Technol 2006, 108:70–83. doi:10.1002/
ejlt.200500272.
30. Jump DB. Dietary polyunsaturated fatty acids and
regulation of gene transcription. Curr Opin Lipidol
2002, 13:155–164. doi:10.1097/00041433-200204000-
00007.
31. Matsuzaka T, Shimano H, Yahagi N, Amemiya-
Kudo M, Yoshikawa T, Hasty AH, Tamura Y,
Osuga J, Okazaki H, Iizuka Y, et al. Dual regulation
of mouse Delta(5)- and Delta(6)-desaturase gene
expression by SREBP-1 and PPARalpha. J Lipid Res
2002, 43:107–114.
32. Meher A, Sundrani D, Joshi S. Maternal nutrition
influences angiogenesis in the placenta through peroxi-
some proliferator activated receptors: a novel hypothe-
sis. Mol Reprod Dev 2015, 82:726–734. doi:10.1002/
mrd.22518.
33. McCarthy FP, Drewlo S, English FA, Kingdom J,
Johns EJ, Kenny LC, Walsh SK. Evidence implicating
peroxisome proliferator-activated receptor-gamma in
the pathogenesis of preeclampsia. Hypertension 2011,
58:882–887. doi:10.1161/hypertensionaha.111. 179440.
 Focus Article
34. McKeegan PJ, Sturmey RG. The role of fatty acids in
oocyte and early embryo development. Reprod Fertil
Dev 2011, 24:59–67. doi:10.1071/RD11907.
35. Burton GJ, Jauniaux E, Charnock-Jones DS. Human
early placental development: potential roles of the
endometrial glands. Placenta 2007, 28(suppl A):
S64–S69. doi:10.1016/j.placenta.2007.01.007.
36. Haggarty P, Wood M, Ferguson E, Hoad G,
Srikantharajah A, Milne E, Hamilton M,
Bhattacharya S. Fatty acid metabolism in human pre-
implantation embryos. Hum Reprod 2006,
21:766–773. doi:10.1093/humrep/dei385.
37. Salleh N. Diverse roles of prostaglandins in blastocyst
implantation. Sci World J 2014, 2014:968141.
doi:10.1155/2014/968141.
38. Lim H, Dey SK. PPAR delta functions as a prostacyclin
receptor in blastocyst implantation. Trends Endocrinol
Metab 2000, 11:137–142. doi:10.1016/S1043-2760
(00)00243-5.
39. Kadam L, Kohan-Ghadr HR, Drewlo S. The balancing
act - PPAR-gamma’s roles at the maternal-fetal inter-
face. Syst Biol Reprod Med 2015, 61:65–71.
doi:10.3109/19396368.2014.991881.
40. Anin SA, Vince G, Quenby S. Trophoblast invasion.
Hum Fertil (Camb) 2004, 7:169–174. doi:10.1080/
14647270400006911.
41. Jauniaux E, Jurkovic D, Campbell S. In vivo investiga-
tions of the anatomy and the physiology of early
human placental circulations. Ultrasound Obstet
Gynecol 1991, 1:435–445. doi:10.1046/j.1469-
0705.1991.01060435.x.
42. Demir R, Seval Y, Huppertz B. Vasculogenesis and
angiogenesis in the early human placenta. Acta Histo-
chem 2007, 109:257–265. doi:10.1016/j.acthis.2007.
02.008.
43. Johnsen GM, Basak S, Weedon-Fekjaer MS, Staff AC,
Duttaroy AK. Docosahexaenoic acid stimulates tube
formation in first trimester trophoblast cells, HTR8/
SVneo. Placenta 2011, 32:626–632. doi:10.1016/j.
placenta.2011.06.009.
44. Finetti F, Solito R, Morbidelli L, Giachetti A, Ziche M,
Donnini S. Prostaglandin E2 regulates angiogenesis via
activation of fibroblast growth factor receptor-1. J Biol
Chem 2008, 283:2139–2146. doi:10.1074/jbc.
M703090200.
45. Basak S, Das MK, Duttaroy AK. Fatty acid-induced
angiogenesis in first trimester placental trophoblast
cells: possible roles of cellular fatty acid-binding pro-
teins. Life Sci 2013, 93:755–762. doi:10.1016/j.
lfs.2013.09.024.
46. Matijevic R, Meekins JW, Walkinshaw SA, Neilson JP,
McFadyen IR. Spiral artery blood flow in the central
and peripheral areas of the placental bed in the second
trimester. Obstet Gynecol 1995, 86:289–292.
doi:10.1016/0029-7844(95)00129-F.
© 2016 Wiley Periodicals, Inc.
wires.wiley.com/devbio
47. Jauniaux E, Watson AL, Hempstock J, Bao YP,
Skepper JN, Burton GJ. Onset of maternal arterial
blood flow and placental oxidative stress: a possible
factor in human early pregnancy failure. Am J Pathol
2000, 157:2111–2122. doi:10.1016/S0002-9440(10)
64849-3.
48. Shoji H, Franke C, Demmelmair H, Koletzko B. Effect
of docosahexaenoic acid on oxidative stress in placen-
tal trophoblast cells. Early Hum Dev 2009,
85:433–437. doi:10.1016/j.earlhumdev.2009.02.003.
49. Stark MJ, Clifton VL, Hodyl NA. Differential effects
of docosahexaenoic acid on preterm and term placen-
tal pro-oxidant/antioxidant balance. Reproduction
2013, 146:243–251. doi:10.1530/REP-13-0239.
50. Jones ML, Mark PJ, Keelan JA, Barden A, Mas E,
Mori TA, Waddell BJ. Maternal dietary omega-3 fatty
acid intake increases resolvin and protectin levels in
the rat placenta. J Lipid Res 2013, 54:2247–2254.
doi:10.1194/jlr.M039842.
51. Jones ML, Mark PJ, Mori TA, Keelan JA, Waddell BJ.
Maternal dietary omega-3 fatty acid supplementation
reduces placental oxidative stress and increases fetal
and placental growth in the rat. Biol Reprod 2013,
88:37. doi:10.1095/biolreprod.112.103754.
52. Catala A. Five decades with polyunsaturated fatty
acids: chemical synthesis, enzymatic formation, lipid
peroxidation and its biological effects. J Lipids 2013,
2013:710290. doi:10.1155/2013/710290.
53. Keelan JA, Mas E, D’Vaz N, Dunstan JA, Li S,
Barden AE, Mark PJ, Waddell BJ, Prescott SL,
Mori TA. Effects of maternal n-3 fatty acid supplemen-
tation on placental cytokines, pro-resolving lipid med-
iators and their precursors. Reproduction 2015,
149:171–178. doi:10.1530/rep-14-0549.
54. Melody SM, Vincent R, Mori TA, Mas E, Barden AE,
Waddell BJ, Keelan JA. Effects of omega-3 and omega-
6 fatty acids on human placental cytokine production.
Placenta 2015, 36:34–40. doi:10.1016/j.placenta.
2014.10.013.
55. Cheng Z, Elmes M, Kirkup S, Abayasekara DR,
Wathes DC. Effects of n-6 polyunsaturated fatty acids
on prostaglandin production in ovine fetal chorion
cells in vitro in late gestation ewes. Placenta 2011,
32:752–756. doi:10.1016/j.placenta.2011.06.026.
56. Gruenwald P. The development of the placental lobu-
lar pattern in the human: review and reinterpretation
of the material. Obstet Gynecol 1977, 49:728–732.
57. Burton GJ, Sebire NJ, Myatt L, Tannetta D, Wang YL,
Sadovsky Y, Staff AC, Redman CW. Optimising sam-
ple collection for placental research. Placenta 2014,
35:9–22. doi:10.1016/j.placenta.2013.11.005.
58. Crabtree JT, Gordon MJ, Campbell FM, Dutta-
Roy AK. Differential distribution and metabolism of
arachidonic acid and docosahexaenoic acid by human
placental choriocarcinoma (BeWo) cells. Mol Cell
 WIREs Developmental Biology
Biochem 1998, 185:191–198. doi:10.1023/A:100685
2230337.
59. Campbell FM, Bush PG, Veerkamp JH, Dutta-
Roy AK. Detection and cellular localization of plasma
membrane-associated and cytoplasmic fatty acid-
binding proteins in human placenta. Placenta 1998,
19:409–415. doi:10.1016/S0143-4004(98)90081-9.
60. Rani A, Meher A, Wadhwani N, Joshi S. Role of
maternal long-chain polyunsaturated fatty acids in pla-
cental development and function. In: Duttaroy AK,
Basak S, eds. Human Placental Trophoblasts: Impact
of Maternal Nutrition. Boca Raton, FL: CRC Press;
2015, 113–128.
61. Jauniaux E, Hempstock J, Greenwold N, Burton GJ.
Trophoblastic oxidative stress in relation to temporal
and regional differences in maternal placental blood
flow in normal and abnormal early pregnancies.
Am J Pathol 2003, 162:115–125. doi:10.1016/s0002-
9440(10)63803-5.
62. Schuhmann RA, Wynn RM. Regional ultrastructural
differences in placental villi in cotyledons of a mature
human placenta. Placenta 1980, 1:345–353.
63. Bacon BJ, Gilbert RD, Longo LD. Regional anatomy
of the term human placenta. Placenta 1986,
7:233–241.
64. Wyatt SM, Kraus FT, Roh CR, Elchalal U,
Nelson DM, Sadovsky Y. The correlation between
sampling site and gene expression in the term human
placenta. Placenta 2005, 26:372–379. doi:10.1016/j.
placenta.2004.07.003.
65. Brameld JM, Hold R, Pipkin FB. Regional variation in
angiotensin converting enzyme activity in the human
placenta. Placenta 2011, 32:906–908. doi:10.1016/j.
placenta.2011.07.085.
66. Mvumbi L, Manci EA, Ulmer D, Shah AK. Glycogen
levels in human term placental disks, umbilical cords,
and membranes. Pediatr Pathol Lab Med 1996,
16:597–605. doi:10.1080/107710496175534.
67. Gratton RJ, Gluszynski M, Mazzuca DM, Nygard K,
Han VK. Adrenomedullin messenger ribonucleic acid
expression in the placentae of normal and preeclamptic
pregnancies. J Clin Endocrinol Metab 2003,
88:6048–6055. doi:10.1210/jc.2003-030323.
68. Roland L, Beauchemin D, Acteau G, Fradette C, St-
Pierre I, Bilodeau JF. Effects of labor on placental
expression of superoxide dismutases in preeclampsia.
Placenta 2010, 31:392–400. doi:10.1016/j.
placenta.2010.02.007.
69. Reddy VM, Geetha SP, Nim VK. Variations in placen-
tal attachment of umbilical cord. J Anat Soc India
2012, 61:1–4. doi:10.1016/S0003-2778(12)80002-5.
70. Yampolsky M, Salafia CM, Shlakhter O, Haas D,
Eucker B, Thorp J. Centrality of the umbilical cord
insertion in a human placenta influences the placental
efficiency. Placenta 2009, 30:1058–1064. doi:10.1016/
j.placenta.2009.10.001.
© 2016 Wiley Periodicals, Inc.
Altered development and function of the placental regions
71. Manci EA, Blackburn WR. Regional variations in the
levels of zinc, iron, copper, and calcium in the term
human placenta. Placenta 1987, 8:497–502.
72. Jendryczko A, Drozdz M, Wojcik A. Regional varia-
tions in the activities of antioxidant enzymes in the
term human placenta. Zentralbl Gynakol 1991,
113:1059–1066.
73. Demir-Weusten AY, Seval Y, Kaufmann P, Demir R,
Yucel G, Huppertz B. Matrix metalloproteinases-2, -3
and -9 in human term placenta. Acta Histochem 2007,
109:403–412. doi:10.1016/j.acthis.2007.04.001.
74. Saleh SA, Maraqa AD, Ali ME, Mustafa ZS,
Qadoumi OF. Regional distribution of superoxide dis-
mutase activity in human placenta and its correlation
with lipid peroxidation. Jordan J Biol Sci 2010,
3:125–132.
75. Abdulsid A, Fletcher A, Lyall F. Heat shock protein
27 is spatially distributed in the human placenta and
decreased during labor. PLoS One 2013, 8:e71127.
doi:10.1371/journal.pone.0071127.
76. Alwarfaly S, Abdulsid A, Hanretty K, Lyall F. Paraox-
onase 2 protein is spatially expressed in the human
placenta and selectively reduced in labour. PLoS One
2014, 9:e96754. doi:10.1371/journal.pone.0096754.
77. Larque E, Demmelmair H, Klingler M, De Jonge S,
Bondy B, Koletzko B. Expression pattern of fatty acid
transport protein-1 (FATP-1), FATP-4 and heart-fatty
acid binding protein (H-FABP) genes in human term
placenta. Early Hum Dev 2006, 82:697–701.
doi:10.1016/j.earlhumdev.2006.02.001.
78. Klingler M, Demmelmair H, Larque E, Koletzko B.
Analysis of FA contents in individual lipid fractions
from human placental tissue. Lipids 2003,
38:561–566. doi:10.1007/s11745-003-1496-8.
79. Yamazaki I, Kimura F, Nakagawa K, Nakai K,
Arima T, Kawabata T, Kagawa Y, Saitoh S, Mizuno S,
Yaegashi N, et al. Heterogeneity of the fatty acid com-
position of Japanese placentae for determining the per-
inatal fatty acid status: a methodological study. J Oleo
Sci 2015, 64:905–914. doi:10.5650/jos.ess15071.
80. Hladunewich M, Karumanchi SA, Lafayette R. Patho-
physiology of the clinical manifestations of preeclamp-
sia. Clin J Am Soc Nephrol 2007, 2:543–549.
doi:10.2215/CJN.03761106.
81. Genbacev O, Joslin R, Damsky CH, Polliotti BM,
Fisher SJ. Hypoxia alters early gestation human cyto-
trophoblast differentiation/invasion in vitro and mod-
els the placental defects that occur in preeclampsia.
J Clin Invest 1996, 97:540–550. doi:10.1172/
JCI118447.
82. Roberts JM, Hubel CA. Is oxidative stress the link in
the two-stage model of pre-eclampsia? Lancet 1999,
354:788–789. doi:10.1016/S0140-6736(99)80002-6.
83. Hirano H, Imai Y, Ito H. Spiral artery of placenta:
development and pathology-immunohistochemical,
 Focus Article
microscopical, and electron-microscopic study. Kobe J
Med Sci 2002, 48:13–23.
84. Boggess KA, Oury TD, Kay HH, Crapo JD. Extracel-
lular superoxide dismutase localization and activity
within the human placenta. Placenta 1998,
19:417–422. doi:10.1016/S0143-4004(98)90082-0.
85. Gratton RJ, Asano H, Han VK. The regional expres-
sion of insulin-like growth factor II (IGF-II) and
insulin-like growth factor binding protein-1 (IGFBP-1)
in the placentae of women with pre-eclampsia. Pla-
centa 2002, 23:303–310. doi:10.1053/plac.2001.0780.
86. Gratton RJ, Gluszynski M, Nygard K, Mazzuca DM,
Graham CH, Han VK. Reducing agent and
tunicamycin-responsive protein (RTP) mRNA expres-
sion in the placentae of normal and pre-eclamptic
women. Placenta 2004, 25:62–69. doi:10.1016/s0143-
4004(03)00216-9.
87. Mistry HD, Kurlak LO, Williams PJ, Ramsay MM,
Symonds ME, Broughton PF. Differential expression
and distribution of placental glutathione peroxidases
1, 3 and 4 in normal and preeclamptic pregnancy.
Placenta 2010, 31:401–408. doi:10.1016/j.placenta.
2010.02.011.
88. Roland-Zejly L, Moisan V, St-Pierre I, Bilodeau JF.
Altered placental glutathione peroxidase mRNA
expression in preeclampsia according to the presence
or absence of labor. Placenta 2011, 32:161–167.
doi:10.1016/j.placenta.2010.11.005.
89. Abdulsid A, Hanretty K, Lyall F. Heat shock protein
70 expression is spatially distributed in human pla-
centa and selectively upregulated during labor and pre-
eclampsia. PLoS One 2013, 8:e54540. doi:10.1371/
journal.pone.0054540.
90. Abdulsid A, Lyall F. Heat shock protein 27 expression
is spatially distributed in human placenta and selec-
tively regulated during preeclampsia. J Reprod Immu-
nol 2014, 101–102:89–95. doi:10.1016/j.jri.2013.
09.002.
© 2016 Wiley Periodicals, Inc.
wires.wiley.com/devbio
91. Alwarfaly S, Abdulsid A, Lyall F. Paraoxonase
3 expression is spatially down-regulated in the human
placenta in labour. Placenta 2014, 35:A65.
doi:10.1016/j.placenta.2014.06.211.
92. Tzschoppe AA, Struwe E, Dorr HG, Goecke TW,
Beckmann MW, Schild RL, Dotsch J. Differences in
gene expression dependent on sampling site in placen-
tal tissue of fetuses with intrauterine growth restric-
tion. Placenta 2010, 31:178–185. doi:10.1016/j.
placenta.2009.12.002.
93. Sahay AS, Sundrani DP, Wagh GN, Mehendale SS,
Joshi SR. Neurotrophin levels in different regions of
the placenta and their association with birth outcome
and blood pressure. Placenta 2015, 36:938–943.
doi:10.1016/j.placenta.2015.06.006.
94. Sahay AS, Sundrani DP, Wagh GN, Mehendale SS,
Joshi SR. Regional differences in the placental levels of
oxidative stress markers in pre-eclampsia. Int J Gynae-
col Obstet 2015, 129:213–218. doi:10.1016/j.
ijgo.2015.03.001.
95. Ghabour MS, Eis ALW, Brockman DE, Pollock JS,
Myatt L. Immunohistochemical characterization of
placental nitric oxide synthase expression in pree-
clampsia. Am J Obstet Gynecol 1995, 173:687–694.
doi:10.1016/0002-9378(95)90324-0.
96. Jauniaux E, Zaidi J, Jurkovic D, Campbell S, Hustin J.
Comparison of colour Doppler features and pathologi-
cal findings in complicated early pregnancy. Hum
Reprod 1994, 9:2432–2437.
97. Yuen RK, Robinson WP. Review: a high capacity of
the human placenta for genetic and epigenetic varia-
tion: implications for assessing pregnancy outcome.
Placenta 2011, 32(suppl 2):S136–S141. doi:10.1016/j.
placenta.2011.01.003.
98. Burdge GC, Lillycrop KA. Fatty acids and epigenetics.
Curr Opin Clin Nutr Metab Care 2014, 17:156–161.
doi:10.1097/MCO.0000000000000023.