European Journal of Clinical Nutrition (2001) 55, 651±656

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Original Communication
Expression of ferritin receptor in placental microvilli membrane
in pregnant women with different iron status at mid-term
gestation
QK Liao1,2, PA Kong1, J Gao1, FY Li1 and ZM Qian2*
1
Department of Pediatrics, The Second University Hospital, The West China University of Medical Sciences, Chengdu, People's Republic
of China; and 2Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong,
People's Republic of China

Objective: The effect of iron status in pregnant women on expression of ferritin receptor in placental microvilli
membrane at mid-term gestation was investigated.
Design: Ferritin receptor binding sites and dissociation constants (Kd) were determined in specimens of placental
microvilli from 30 pregnant women at mid-term gestation and six women at term-delivery.
Results: The ferritin receptor binding sites in the placental microvilli membrane in pregnant women with mild iron
de®ciency and moderate iron de®ciency anemia were signi®cantly higher then those in pregnant women with
normal iron status. However, no signi®cant difference was found between pregnant women with severe iron
de®ciency anemia and with normal measurements. No signi®cant differences of Kd values were detected between
pregnant women with normal iron status and those with iron-de®ciency. Data also revealed that the ferritin
receptor binding sites in placental microvilli membrane and Kd values at mid-term gestation did not differ
signi®cantly from those at term gestation.
Conclusion: Lower iron status in pregnant women could lead to an increase in expression of ferritin receptor in
placental microvilli membrane at mid-term gestation while the dissociation constant of ferritin receptor remains
unchanged. This implies that the regulation of maternal ± fetal iron homeostasis via the ferritin receptor-mediated
pathway is achieved by changes in the numbers of ferritin receptors rather then binding properties.
Sponsorship: China Natural Science Foundation and The Hong Kong Polytechnic University.
Descriptors: ferritin receptor; placental microvilli; iron status; pregnant women; maternal-fetal iron homeostasis
European Journal of Clinical Nutrition (2001) 55, 651±656

Introduction with an increased cases of prematurity and perinatal mor-

Iron de®ciency anemia is the most prevalent nutritional
problem in the world. During their reproductive years and
particularly during pregnancy women are at high risk for
iron de®ciency anemia. In developing countries, the pre-
valence of iron de®ciency anemia in pregnant women
ranges from 35% to 75% (WHO, 1992). The prevalence
of pregnant women suffering from iron de®ciency with or
without anemia is reported to be as high as 40 ± 90% (Li
et al, 1996). A number of studies have indicated that iron
de®ciency anemia during pregnancy may be associated
tality (Lops et al, 1995; Allen, 2000; Rush, 2000; Yip,
2000). However, how iron de®ciency in pregnant women
affects the iron metabolism and iron status of their fetuses
remains to be established. In this study, we investigated the
effect of iron status of pregnant women on the expression
of a ferritin receptor (FnR) in the placental microvilli
membrane at mid-term gestation. The possible roles of
placental FnR in iron transport across the placenta and
the in¯uences of iron de®ciency in pregnant mothers on the
iron status of their fetuses were discussed.

*Correspondence: ZM Qian, Department of Applied Biology and Methods

Chemistry Technology, The Hong Kong Polytechnic University, Kowloon,
Hong Kong, People's Republic of China.
E-mail: bczmqian@polyu.edu.hk
Received 25 August 2000; revised 5 January 2001;
accepted 17 January 2001
Grouping criteria
The procedures of this study received ethical approval from
the research committee of West China University of
 Expression of ferritin receptor
QK Liao et al
652
Table 1 Grouping criteria
Hb SF
Groups (g=l) (mg=l) (ag=RBC)
G1 normal  110  20  6.5
G2 mild IDa  110 12 ± 20  6.5
G3 moderate IDAb 90 ± 110 12 ± 20 or  6.5
G4 severe IDA 60 ± 90
Multiple criteria are more sensitive and speci®c in de®ning iron de®ciency than any one single criterion and therefore
are used in this study. Women were considered to have iron de®ciency anemia when, besides a hemoglobin (Hb) value
of  110 g=l (moderate anemia) or  90 g=l (severe anemia), they also ful®lled any two or more of independent
indicators (serum iron, TIBC and TS), as well as decreased SF and=or decreased EF. The SF level of 20 mg=l was used
as the cut-off point for iron de®ciency according to CAPH criteria (refer to `Methods' section for details).
a
ID, Iron de®ciency; bIDA, iron de®ciency anemia.
Medical Sciences. All pregnant women participating in this
study did so voluntarily. The purpose of the study was
explained and informed consent was obtained. Thirty
pregnant women at mid-term gestation were divided into
four groups: G1, normal measurements; G2, mild iron
de®ciency; G3, moderate iron de®ciency anemia; and G4,
severe iron de®ciency anemia. The grouping criteria are
summarized in Table 1. Because multiple criteria are more
sensitive and speci®c to de®ne iron de®ciency than any one
single criterion (Rusia et al, 1999), in this study multiple
criteria were used. Women were considered to have iron
de®ciency anemia when, besides a hemoglobin (Hb) value
of  110 g=l (moderate anemia) or  90 g=l (severe
anemia), they also ful®lled two or more of the following
independent indicators: serum iron  10.7 mmol=l, total iron
binding capacity (TIBC)  62.7 mmol=l, and transferrin
saturation (TS)  0.15, as well as decreased serum ferritin
(SF)  20 mg=l and=or decreased erythrocyte ferritin
(EF)  6.5 ag=RBC (see Table 1). The SF level of 20 mg=l
was used as the cut-off point for iron de®ciency in this
study according to CAPH (Chinese Association of Pediatric
Hematology) criteria (Liao et al, 1992; Lin, 1995). This
cut-off level was achieved based on a large-scale investiga-
tion of the relationship between SF and stainable bone
marrow iron. Specimens of the placentas of 30 pregnant
women at mid-term gestation were collected with thera-
peutic abortion. Before abortion, maternal peripheral blood
samples were obtained via venipuncture for the measure-
ments of Hb, serum iron, TIBC, TS, SF and EF. In addition,
the specimens of placenta were collected at term delivery
from six different pregnant women with normal measure-
ments of iron indicators, as described in G1 for the
determination of FnR expression.
Assessment of iron status
Serum iron and TIBC were determined by using commer-
cial kits (Sigma, St Louis, MO, USA; Qian et al, 1999). TS
was calculated by the formula: TS ˆ SI=TIBC (%). SF was
quantitated by ELISA, using kits from RAMCO Labora-
tories, Houston, TX, USA. EF was determined by the
method described by Ohhara (1993) with some modi®ca-
tion. Brie¯y, heparin anticoagulated blood was diluted with
European Journal of Clinical Nutrition
EF Serum iron TIBC TS
(mmol=l) (mmol=l) (%)
 10.7  62.7  15
Any two items below normal
Same as the above
Same as the above
two volumes of normal saline and then passed through
degreasing cotton column to remove white blood cells. Red
blood cells were washed twice with heparinized normal
saline and them centrifuged for 10 min. The supernatant
was discarded and the precipitated red cell pellet was
diluted with normal saline to a cell concentration of 2 ±
41012=l. After thawing (ÿ20 C) three times and being
centrifuged for 10 min, the supernatant was collected for
the measurement of ferritin concentration by using the
same assay for the determination of serum ferritin. EF
was calculated by the formula: EF ˆ measured value
(mg=l)=RBC concentration.
Preparation of membrane
Protein of placental microvilli membrane was prepared
according to the procedures of Smith et al (1974, 1977)
and Smith and Brush (1978) with some modi®cation (Liao
et al, 1992; Luo et al, 1996). In brief, portions of placenta
(about 50 g) were rinsed rapidly in ice-cold Kreb's physio-
logical saline to remove much of the blood. The tissue was
gently spread out manually and stirred in 500 ml ice-cold
0.9% NaCl so that the chorionic villi ¯oated out and were
well irrigated by the saline. After 30 min gentle agitation at
0 C using a magnetic stirrer, the saline wash was decanted
and centrifuged, ®rst at 800 g for 10 min to remove tissue
fragments and red blood cells, and then at 10 000 g for
1 min to remove miscellaneous particles. Finally, the still
cloudy supernatant was centrifuged at 50 000 g for 1 h,
when a clear jelly-like pellet was obtained. Electron micro-
scopy of this pellet revealed that it was a homogeneous
collection of membrane vesicles. Enzyme membrane mar-
0
kers, alkaline phosphatase (3.1.6.1) and 5 -nucleotidase
(3.1.3.5), were measured by a modi®cation of the method
of Sterling et al (1964) and by the method of Michell and
Hawthorne (1965) respectively, and found to be consider-
ably enriched in the microvillous preparation. The prepara-
tion is indeed a syncytiotrophoblast plasma membrane.
Determination of ferritin receptor binding sites
The 125I-apoferritin was prepared by the one-step linkage
labeling with horse spleen apoferrin, 125I-Na, and Bolton-

Hunter-reagent (Sigma) (Luo et al, 1996). The binding of
125
I-apoferritin with placental microvilli membrane was
analyzed by radioligand assay as previously described
(Liao et al, 1992; Luo et al, 1996). In brief, placental
microvilli protein (160 mg) and 125I-apoferritin (80 ng) were
added to test tubes numbered from 1 to 10. Unlabeled
apoferritin 0.5 ± 80 mg was added to test tubes of nos 2 ± 9,
and test tube no. 10 was designated as a nonspeci®c binding
tube to which 120 mg of apoferritin was added. The total
reaction volume in all of test tubes was adjusted to 0.5 ml
using isotonic 0.01 M Tris ± HCl solution (pH 7.4) contain-
ing 0.1% bovine serum albumin (BSA). After total radio-
activity (T) was detected by a Geiger counter, each test tube
was incubated in 37 C for 30 min in a shaking water bath
and underwent a regular shaking every 5 min. Reactions
were terminated in an ice incubator, and then 0.1 ml
isotonic 0.01 M Tris ± HCl (pH 7.4) containing 0.084% g-
globulin and 0.6 ml of 12% PEG were added into each tube.
After having been mixed completely and then left undis-
turbed at 4 C for 1 h all of the tubes were centrifuged for
30 min (3500 rpm) and the supernatant was discarded. Then
the precipitant radioactivity (B) was detected. The speci®c
B=T was calculated. The inhibition curve was plotted with
the unlabeled apoferritin concentration as transverse axis
and the speci®c B=T as longitudinal axis. Finally, the FnR
binding sites per milligram of placental microvilli protein
and the dissociation constant (Kd) of FnR were calculated
by the Scatchard plotting method, employing the DP.EXE
software.
Results
Characteristics and indicators of iron status of study
samples
The pregnant women ranged in age from 21 to 36 y, with an
average of 27  10.9 y. None of women smoked cigarettes,
Expression of ferritin receptor
QK Liao et al
653
and alcohol consumption was rare. The gestational ages of
G1 (normal group), G2 (mild iron de®ciency), G3 (moder-
ate iron de®ciency anemia) and G4 (severe iron de®ciency
anemia) were 20.7  3.9, 21.6  3.9, 21.2  3.7 and
20.2  2.6 weeks, respectively (Table 2). The weight of
the pregnant women was measured to the nearest 0.1 kg
with a battery-powered digital scale (Chengdo, SC, PRC),
being 49.3  4.0, 48.0  4.7, 48.2  2.9, and 46.8  3.0 in
G1, G2, G3 and G4, respectively. Height was determined to
the nearest 0.1 cm with a stationary height board fastened to
the wall, being 1.67  0.06, 1.57  0.06, 1.60  0.04 and
1.56  0.04 in G1, G2, G3 and G4, respectively. Parity of
all women in this study was 1. The measurements of
indicators of iron status of study samples in different
groups, including Hb, serum iron, TIBC, TS, SF and EF
are listed in Table 2.
Iron status in pregnant women and ferritin receptor
expression in placental microvilli membrane at
mid-term gestation
The specimens of placenta of pregnant women at mid-term
gestation were collected with therapeutic abortion. Placen-
tal microvilli membrane was prepared and FnR binding sits
were determined. The results showed that FnR binding sites
in G1, G2, G3 and G4 are 9.63  4.72, 15.28  8.36,
14.44  6.13 and 9.37  6.37, respectively. The pregnant
women in G2 and G3 have a signi®cant higher number of
FnR binding sites than those in G1 (both P < 0.05). This
implies that mild iron de®ciency and moderate iron de®-
ciency anemia can lead to an increase in the expression of
FnR in placental microvilli membranes in pregnant women
at mid-gestation. No signi®cant difference was found
between the FnR binding sites of G1 and G4 (P > 0.25).
This result suggests that severe iron de®ciency anemia in
pregnant women at mid-gestation has no such effect on
FnR expression. The dissociation constants (Kd) were
9.47  5.27, 10.36  3.76, 9.22  1.45 and 8.57  4.20 in

Table 2 Characteristics and iron status indicators of study samples

a
Group (n) 1(9) 2(9) 3(8) 4(4)

Height (m) 1.57 0.06 1.57 0.06 1.60 0.04 1.56 0.04
Weight (kg) 49.3 4.0 48.0 4.7 48.2 2.9 46.8 3.0
BMI (kg=m2) 21.0 2.3 21.9 2.8 21.4 2.0 20.8 1.7
Gestational age (weeks) 20.7 3.9 21.6 3.9 21.2 3.7 20.2 2.6
Hb (g=l) 116.7 7.3 113.0 2.6 92.4 3.4 71.2 2.2
Serum iron (mmol=l) 15.3 3.78 7.3  1.83 6.69 1.58 5.50 2.47
TIBC (mmol=l) 37.98 5.49 46.02 14.65 46.98 13.88 46.70 12.53
TS (%) 40.5 9.1 18.2 5.9 14.4 4.3 11.6 3.2
SF (mg=l) 52.8 19.7 19.7 5.4 13.5 4.8 5.58 2.2
EF (ag=RBC) 22.39 7.94 3.47 2.09

Weight was measured to the nearest 0.1 kg with a battery-powered digital scale and height was determined to the nearest
0.1 cm with a stationary height board fastened to the wall. The parity of all women in this study was 1. Maternal
peripheral blood samples were obtained before abortion for the measurements of Hb, serum iron, TIBC, TS, SF and EF.
The results are means s.d.
a
Group 1, Normal iron status; group 2, mild iron de®ciency; group 3, moderate iron de®ciency anemia; Group 4, severe
iron de®ciency anemia.

European Journal of Clinical Nutrition

 Expression of ferritin receptor
QK Liao et al
654
Table 3 Ferritin receptor (FnR) binding sites and dissociation constants (Kd) in different groups at mid-
term and at term gestation
Groupsa (n)
Mid-term G1 (9)
Mid-term G2 (9)
Mid-term G3 (8)
Mid-term G4 (4)
Term pregnancy (6) (normal iron status)
The results are means s.d.
a
G1, normal iron status; G2, mild iron de®ciency; G3, moderate iron de®ciency anemia; G4, severe iron
de®ciency anemia; term pregnancy, specimens of placenta were collected from pregnant women at term
delivery with normal measurements of iron indicators as described in G1.
*P < 0.05 vs group 1.
G1, G2, G3 and G4, respectively. No signi®cant difference
was detected between normal pregnant women and those
with iron de®ciency or iron de®ciency anemia (Table 3).
Ferritin receptor expression and dissociation constant (Kd)
in placental microvilli membrane at mid-term and at term
gestation
To determine the effect of gestation time on expression of
FnR, the six specimens of placenta were also collected
from six pregnant women at term delivery with normal
measurements of iron indicators as described in G1, and the
FR binding sites and dissociation constants (Kd) were
investigated. The FnR binding site in term pregnancy
with normal iron measurements was 9.87  4.72 and dis-
sociation constant (Kd) was 7.99  3.23 respectively (Table
3). No signi®cant difference was found compared to the
corresponding values in mid-term pregnancy with normal
iron status (both P > 0.25). The results revealed that the
gestation time has no signi®cant effect on the expression of
FnR and dissociation constant values in placental microvilli
membrane in pregnant women (Table 3). There were no
signi®cant interactions between term pregnancy and mid-
term pregnancy for any variables.
Discussion
The placenta is of pivotal importance for the intrauterine
development of a fetus and is the essential organ of
substance transportation to the fetus. Well-developed pla-
cental microvilli and intact placental blood circulation are
prerequisites for adequate substance transfer across the
placenta. Previous studies including ours (Loh et al,
1980; Tawada et al, 1985; Takami et al, 1986; Contractor
& Eaton, 1986; Liao et al, 1992; Allen, 2000) have
con®rmed that placental microvilli membrane abounds in
transferrin receptor (TfR), an important iron transport
protein. This protein plays a key role in iron transport
from the maternal to the fetal circulation (Tawada et al,
1985; Contractor & Eaton, 1986; Liao et al, 1992; Allen,
2000). TfR has two binding sites for diferric transferring
European Journal of Clinical Nutrition
FnR binding sites Dissociation constants (Kd)
(1012=mg protein) (10ÿ8M)
9.63 4.72 9.47 5.27
15.28 8.36* 10.36 3.76
14.44 6.13* 9.22 1.45
9.37 6.37 8.57 4.20
9.87  4.72 7.99 3.23
(Tf). Tf-TfR complex enters the cell via endocytosis (Qian
& Tang, 1995; Qian et al, 1997). In endosome, iron is
released from Tf and enters cytosol to take part in impor-
tant biochemical processes such as Hb biosynthesis. The
TfR then returns to cell membrane for re-utilization and re-
uptake of Tf-bound iron (Tf-Fe). In placenta, serum Tf
carries iron from the maternal circulation to TfR located on
the apical surface of the placental syncytiotrophoblast,
holoTf is endocytosed, iron is released, and apoTf is
returned to the maternal circulation. The free iron then
binds to ferritin in placental cells where it is transferred to
apoTf, which enters from the fetal side of the placenta and
exits as holoTf into the fetal circulation (Allen, 2000).
Extensive studies indicate that an increase in the expression
of TfR in placental microvilli might be a result of a
compensatory mechanism with regard to iron de®ciency
and mild iron-de®ciency anemia in pregnant mothers
(Huebers, 1990). However, the function of this compensa-
tory system is believed to be limited based on the fact that
the Tf saturation is remarkably decreased and the TfR
expression is also hindered in pregnant women with
severe iron de®ciency (Singla et al, 1996; Allen, 2000).
In addition, it was reported that iron status in fetuses whose
mothers were suffering from iron de®ciency is normal or
nearly normal, being independent of maternal iron status
(Gebre-Medhin & Birgegard, 1981; Dallman, 1989; Bhar-
gava et al, 1991; Lao et al, 1991; Institute of Medicine,
food and Nutrition Board, 1993; Hokama et al, 1996),
although different results have been reported (Blot et al,
1999). These ®ndings imply that there might be some other
mechanisms involved in the regulation of maternal-fetal
iron transport.
Previous studies have demonstrated that FnR, in addi-
tion to TfR, is present on the membranes of many normal
cells (Moss et al, 1992), including reticulocytes (Blight and
Morgan, 1987a), lymphoblasts (Adams et al, 1992), liver
(Moss et al, 1988) and brain cells (Adams et al, 1992;
Ramm et al, 1994; Hulet et al 1999). This protein is also
found to play a role in iron transport across the membrane
of these cells (Blight and Morgan, 1987b; Moss et al, 1988;
Osterloh & Aisen, 1989; Gelvan et al, 1996) and ferritin
uptake by human erythroid precursors is a regulated iron

uptake pathway (Gelvan et al, 1996). On the human
placental microvillous membrane, the present of FnR has
been well documented (Celada et al, 1980; Tawada et al,
1985; Takami et al, 1986; Contractor & Eaton, 1986; van
Dijk, 1988). A study of indirect immuno¯uorescence
(Brown et al, 1979) shows that ferritin in placenta micro-
villi plays an important role in the transportation of
maternal iron across the placenta. Tawada et al (1985)
reported that iron is transferred from the mother to the fetus
by the placental active function, and both TfR and FnR on
trophoblasts participate in the adequate placental iron
transport. Takami et al (1986) presumed that placental
FnR could be another regulatory pathway of maternal ±
fetal iron transfer based on their study. Okuyama et al
(1985) demonstrated that FnR is present in every level of
the trophoblast and suggested that FnR might act as a safety
valve, regulating the transferred iron between mother and
fetus and assuring a constant iron supply. An animal study
in pregnant guinea pigs also revealed that ferritin-bound
iron could be taken up by the placenta (Lamparelli et al,
1989). Aisen (1991) pointed out that the placental FnR
mediated-iron transfer pathway might be an alternative or a
compensatory mechanism for cell iron supply when the
TfR-mediated pathway was inadequate.
Based on the above studies and the results of the present
study, it might be reasonable to propose that FnR-mediated
iron uptake by placental trophoblasts constitutes an iron
transport pathway in addition to the classical TfR-mediated
uptake pathway. It is highly likely that both might be the
regulated iron uptake pathways in the placenta and could
act coordinately to maintain adequate iron transport across
the placenta. In pregnant women with normal iron status,
maternal iron would be transferred to placental microvilli
syncytial cells in the form of diferric Tf-TfR complex and
ferritin-FnR complex. In such a case, the expression of both
TfR and FnR is normal. In pregnant women with mild iron
de®ciency and moderate iron de®ciency anemia, iron trans-
port across the placenta via the TfR pathway might be
adversely affected due to the unavailability of Tf-Fe with
low Tf saturation. Therefore, expression of placental FnR
and FnR-mediated iron uptake would increase, as revealed
by our present study. The compensatory increase in FR-
mediated iron transport would be able to keep a constant
iron supply from mother to fetus, although pregnant women
with mild iron de®ciency and moderate iron de®ciency
anemia have `inadequate' iron. It is probably the reason
why iron status in fetuses whose mother is suffering from
iron de®ciency is normal or nearly normal, as reported by
some research groups (Gebre-Medhin & Birgegard, 1981;
Dallman, 1989; Bhargava et al, 1991; Lao et al, 1991;
Institute of Medicine, Food and Nutrition Board, 1993;
Hokama et al, 1996). Our results also show that there is no
signi®cant difference in FnRs between pregnant women
with severe iron de®ciency anemia and with normal mea-
surements. The cause is unclear. However, it is possibly
associated with severe iron de®ciency itself. It has been
reported (Finch et al, 1983) that low levels of plasma iron,
Expression of ferritin receptor
QK Liao et al
655
as found in severe iron de®ciency, could result in damage
to fetal tissues and reduced capacity of placental tissues to
take up iron. Singla et al (1996) demonstrated that a mild
degree of maternal anemia has little in¯uence on iron
accretion in the fetus. However, with increasing severity
of maternal anemia, the fetus accumulates less and less
iron, and levels of serum iron, Tf saturation and ferritin in
the cord blood of severely anemic women is markedly
decreased. It is likely that severe iron de®ciency anemia
itself, in addition to being able to reduce TfR expression in
pregnant women (Singla et al, 1996; Allen, 2000), could
damage the placenta and thus inhibit FnR expression.
Further investigations are needed.
The results also revealed that the dissociation constant
of FnR in placental microvilli membrane at mid-term
gestation remained unchanged regardless of maternal iron
status. This indicates that the regulation of maternal ± fetal
iron homeostatis via the FnR-mediated pathway was
achieved by changes in the numbers of FnR rather than
binding ability. In addition, our result showed that, in
pregnant women with normal iron status, ferritin binding
sites and Kd values in placental microvilli membrane at
mid-term gestation did not differ signi®cantly from those at
term gestation. It indicates that FnRs in placental microvilli
play a very important role in the regulation of iron transport
across the placenta, starting at least from the mid-stage of
pregnancy. Adequate iron transport across the placenta
might be maintained by the coordinate actions of the
well-developed TfR-mediated pathway as well as the
FnR-mediated pathway under normal conditions.
Acknowledgements ÐThis study was supported by China Natural Science
Foundation and the Hong Kong Polytechnic University grants (A=C:
A-P136 and A-PA 79).
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