Placenta (2004), 25, Supplement A, Trophoblast Research, Vol. 18, S3–S9
doi:10.1016/j.placenta.2004.01.011
What Can Comparative Studies of Placental Structure Tell Us?—
A Review
A. C. Enders a,* and A. M. Carter b
a
Department of Cell Biology and Human Anatomy, University of California, School of Medicine, One Shields Avenue, Davis,
CA 95616, USA; b Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark
Paper accepted 2 January 2004
The diversity of placental structures in Eutherian mammals is such that drawing generalizations from the definitive forms is
problematic. There are always areas of reduced interhaemal distance whether the placenta is epitheliochorial, synepitheliochorial,
endotheliochorial or haemochorial. However, the thinning may be achieved by different means. The presence of a haemophagous
area as an iron transport facilitator is generally associated with endotheliochorial placentae but is also found in sheep and goats
(synepitheliochorial) and in tenrecs and hyaenas (haemochorial). Although similar chorioallantoic placentae are found within
families, structure begins to diverge at the ordinal level and there is little correlation at the supraordinal level of phylogeny.
Differences in formation and function of the yolk sac provide additional variation. There would appear to be considerable adaptive
pressure for development or retention of the haemochorial type of chorioallantoic placenta. This type of placenta has several
possible drawbacks including more ready passage of fetal cells to the maternal organism and, should the haemochorial condition
be achieved early, oxidative stress. At any rate no animal larger than the human and gorilla has this type of placenta. The
endotheliochorial condition is found in animals as large as the bears, manatee and elephants. In addition to the ungulates, the
epitheliochorial condition is present in the largest animals with the longest gestation periods, the whales. Considering the length
of time since the early stages of mammalian evolution, it is probable that few unmodified structural features are present in any
currently surviving mammal. Nevertheless, more complete studies of divergent types of mammalian placenta should help our
understanding of mammalian interrelationships as well as placental function.
2004 IFPA and Elsevier Ltd. All rights reserved.
Placenta (2004), 25, Supplement A, Trophoblast Research, Vol. 18, S3–S9
INTRODUCTION
One of the more surprising and interesting results of recent
research is the conservation throughout the animal kingdom
of genes. Thus numerous distinct Wnt oncogenes occur in
Drosophila, zebrafish, Xenopus, chick and mouse, and Wnt2
appears to participate in normal placental development in the
mouse [1]. Consequently the large numbers of genes currently
being discovered and analysed in mouse development [2,3] can
be expected to be present in development in other mammals.
Of course small variations in DNA of individual genes between
species, factors controlling the time of expression and even
microRNA repression of gene expression can be expected to
add to diversity [4]. Although genes such as Indian hedgehog
Ihh [5] may participate in both Drosophila and mouse development, the latter animals neither fly nor lay eggs. In contrast
we are faced with a nearly overwhelming diversity of methods
of implantation of the blastocyst and structure of the placenta.
Can we in fact deduce any generalizations from observation of
placental structure?
*
To whom correspondence should be addressed. Tel.: +1-530-7528719; Fax. +1-530-752-8520; E-mail: acenders@ucdavis.edu
0143-4004/$–see front matter
INTERHAEMAL DISTANCES
First, some of the more obvious conclusions. It is now well
established that the number and nature of the layers between
fetal and maternal blood bear no relationship to the placenta’s
ability to provide oxygen to the fetus. Wooding and Flint [6],
in their chapter in Marshall’s Physiology of Reproduction,
tabulate the way in which all of the chorioallantoic placental
types—epitheliochorial, synepitheliochorial, endotheliochorial
and haemochorial—have areas of comparable proximity of the
two blood streams reducing the diffusion distance. The way in
which the interhaemal area is reduced varies in part with
definitive placental type (Figure 1). In epitheliochorial and
synepitheliochorial placentae the indenting of both trophoblast
and uterine epithelium by capillaries decreases the interhaemal
distance. In endotheliochorial placentae the indentation of
trophoblast by fetal vessels within the labyrinth is the primary
method of reducing interhaemal distance [7]. In haemochorial
placentae thinning is achieved by a number of ways of reducing
the thickness of the trophoblast; these include wide spacing of
nuclei (elephant shrew), confining some of the trophoblast in
contact with maternal blood to a spongy zone or interstitial
area as in myomorph and histricognath rodents [8], alternating
2004 IFPA and Elsevier Ltd. All rights reserved.
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Placenta (2004), Vol. 25, Supplement A, Trophoblast Research, Vol. 18
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Figure 1. Micrographs of the definitive interhaemal areas in different types of placenta. (A) Diffuse epitheliochorial placenta of the bush baby (Galago). The taller
light-staining trophoblast cells are closely apposed to the dark maternal epithelium. Note that fetal capillaries (arrows) indent the trophoblast, thinning the distance
between the maternal vessel (mv) and the fetal vessels. (B) Synepitheliochorial placenta of the cow. Binucleate cells (arrows) are seen in the trophoblast. A
trinucleate cell formed by fusion of a binucleate cell and uterine epithelial cell is also seen (asterisk) near maternal capillaries (arrowheads). (C) Endotheliochorial
placenta of the African elephant (Loxodonta). Fetal vessels (arrows) indent the trophoblast adjacent to the maternal vessels (mv). (D) Endotheliochorial placenta
of the mink. Note the hypertrophied endothelial cells in the maternal vessel (mv) and the indentation of the trophoblast by fetal vessels (arrows). (E)
Haemomonochorial placenta of the woodchuck (Marmota). Note the segregation of many of the trophoblast nuclei into clusters or knots (arrows), resulting
in thinner syncytial trophoblast lining the maternal blood spaces (mbs). (F) Cellular haemomonochorial placenta of the jumping mouse (Zapus). The interhaemal
area between fetal capillary (fc) and maternal blood spaces (mbs) has a single layer of giant trophoblast cells with abutting thin processes between perinuclear
regions. 400.
Enders and Carter: Comparative Placental Structure
thick and thin regions (rabbit), and accumulating nuclei in
syncytial knots (many primates, marmot, hyaena) [9].
MORPHOLOGICAL EVIDENCE OF IRON
TRANSFER
Considerable information is available on different ways in
which iron can be transferred to the developing fetus. In
epitheliochorial placentae such as those of the pig [10], horse
[11] and possibly galago [12], uterine secretions in the form
of uteroferrin provide a major source of iron to the trophoblast. Yet the goat and sheep have haemophagous areas
that apparently facilitate iron transport [13]. Mammals with
endotheliochorial placentae such as the carnivores (except the
hyaena), shrews, elephants and some bats, have specifically but
divergently situated haemophagous areas [14]. Nevertheless
there are some species such as Dipodomys that have an
endotheliochorial placenta but no haemophagous area [15]; the
pathway of iron transfer in this species is unknown. There are
species with haemochorial placentae that also have large
haemophagous areas such as several of the tenrecs [16]. On the
other hand many species with haemochorial placentae use
maternal and fetal transferrins and an elaborate receptor
endocytosis and release mechanism as a major transfer system
[17]. Some rodent species also use yolk sac transfer, especially
early in gestation [18]. It would be interesting to know what
pathways of iron transfer are present in a primitive mammal
such as the armadillo with its villous haemochorial placenta
and inverted yolk sac.
PHYLOGENETIC RELATIONSHIPS
It is abundantly clear that closely related species have similar
definitive placental structure. For example, all 285 genera
of the rodent family Muridae may be expected to have
haemotrichorial chorioallantoic placentae, although only about
a dozen species have been examined to date [19]. The general
rule that all genera within a family have similar placentae
might be thought to have an exception in the mole family
Talpidae. The American mole Scalopus is considered to have
an epitheliochorial placenta [20], whereas the European mole
Talpa is definitely endotheliochorial [21]. However, only a
single midgestation specimen of Scalopus was available for
examination by electron microscopy, and the looping arrangement of the maternal vessels is more similar to that seen in
endotheliochorial placentae than that in typical epitheliochorial
placentae. Within many but by no means all orders of
mammals different families have similar placentae. Carnivores,
with the hyaena as the exception, all have endotheliochorial
placentae but the position of the haemophagous area and
the presence or absence of decidual cells vary. Artiodactyls
have either epitheliochorial or synepitheliochorial placentae;
perissodactyls have diffuse epitheliochorial placentae but not
all have endometrial cups [6]. The bats (Chiroptera) have
either endotheliochorial or haemochorial placentae, primates
S5
either epitheliochorial or haemochorial placentae. Nearly all
members of the most abundant order, Rodentia, have haemochorial placentae. The sciuromorphs and hystricomorphs
have similar but distinct types of syncytial haemomonochorial
placentae. The vast majority of myomorph rodents have
haemotrichorial placentae; however, both cellular haemomonochorial and endotheliochorial placentae are present in this
group [9,14].
Using placental structure to aid in analysing relationships
between orders is more problematic. The recent use of
mitochondrial and nuclear DNAs to analyse interordinal
relationships has elicited renewed interest in phylogeny and
increased the search for morphological similarities [22]. These
studies place several groups in the Afrotheria, linking such
seemingly diverse species as the tenrecs with the elephants
[23]. If we accept the premise that there are four superorders
(Afrotheria, Laurasiatheria, Euarchontoglires, Xenarthra)
based on mitochondrial DNA and geographic regions of
evolution, it can be seen that the definitive interhaemal
structures bear little relationship to the superorders (Table 1).
Luckett [24] suggested a cladistic approach using multiple
developmental aspects (formation of the amniotic cavity,
size of allantois, yolk sac development, etc.) and assigning
these features to primitive (i.e. similar to reptiles) or derived
(advanced) categories as a means of assessing relationships.
This approach, taking into account the way in which extraembryonic membranes are formed, provides appreciably more
information than just considering definitive placental form.
Unfortunately the information on early development of such
membranes is even more spotty than that on the definitive
form of the chorioallantoic placenta.
Not surprisingly the Eutherian yolk sac, freed of its
relationship to yolk uptake, takes a variety of forms. It retains
the primitive function of blood cell formation and some
synthetic and uptake function but also specializes in a variety
of fashions [25]. The yolk sac can invert to make uptake from
uterine secretion more direct as in rats, guinea pigs, rabbits,
armadillos and others. Some of its original cells can be used to
form the earliest extraembryonic mesoderm as in higher
primates [26,27]. The function of the mesothelium and endoderm can be modified as in some species of bats in which
the mesothelium becomes an endocytic epithelium and the
glandular aspect of the endoderm is emphasized [25,28]. It
should be noted that a ‘free’ yolk sac (not attached to the
trophoblast) can still participate in uptake functions. Even the
secondary yolk sac of haplorhine primates appears to have
absorptive functions [29].
Mossman [14] attempted to group Eutherian taxa by their
definitive yolk sac structure; he divided the types of yolk sacs
into three major groups with nine subgroups. Using this
system of classification, bat families were found in all three
major groups, and one of the nine minor groups consisted of
vespertilionid bats, tree shrews, and golden moles. This lack of
conformity with other means of classification further indicates
both the variation that can occur in yolk sac structure and its
derived nature.
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Placenta (2004), Vol. 25, Supplement A, Trophoblast Research, Vol. 18
Table 1. Placental types in superorders and orders
Placenta type
Superorder
Order
Haemochorial
Laurasiatheria
Carnivora—hyaenas only
Chiroptera—many bat families
Insectivora—hedgehogs
Rodentia—most families
Lagomorpha—rabbits, pikas
Primata—monkeys, gorillas, man, Tarsius
Dermoptera—flying lemurs
Xenarthra—armadillos, anteaters
Hyracoidea—hyraxes, conies
Afrosoricida—tenrecs, golden moles
Macroscelidea—elephant shrews
Carnivora—all but hyaena
Pinnipedia—seals, walruses
Chiroptera—several bat families
Insectivora—shrews
Rodentia—kangaroo rat
Scandentia—tree shrews
Xenarthra—sloths
Proboscidea—elephants
Tubulidentata—aardvark
Sirenia—manatee
Cetacea—whales, porpoises
Artiodactyla—cows, pigs, deer
Perissodactyla—horses, tapirs
Pholidota—pangolin
Primata—lemurs, lorises
Euarchontoglires
Xenarthra
Afrotheria
Endotheliochorial
Laurasiatheria
Euarchontoglires
Xenarthra
Afrotheria
Epitheliochorial
Laurasiatheria
Euarchontoglires
ADVANTAGES AND DISADVANTAGES OF
PLACENTAL ARRANGEMENT
Haemochorial placentae
The evolutionary pressure favouring some type of haemochorial placenta has obviously been extreme. Haemochorial
placentae are found in insectivores, primates, tenrecs, rodents,
bats, hyraxes, elephant shrews, anteaters, armadillos, flying
lemurs and even hyaenas. The large variation in the definitive
form of the placenta, the divergent way in which the haemochorial condition is achieved, and the variety of unrelated
orders in which it is found suggest considerable convergent
evolution.
Many of the advantages of the haemochorial relationship are
quite obvious. Not only does the haemochorial placental type
provide direct access to maternal blood for oxygen–CO2
exchanges between it and trophoblast, but more importantly it
places the surface of the trophoblast with its receptors for
glucose [30] and amino acids [31,32] in contact with maternal
blood facilitating maternal-fetal transport. Water and inorganic
ions that participate in cotransport or are necessary for skeletal
development are also directly available [33]. Trophoblast in
this position also participates in active receptor-mediated
transfer of IgG, possibly by molecular binding of the IgG that
has been internalized by endocytosis [34,35]. It also provides
direct access to the maternal organism for hormones derived
from the fetus and trophoblast. In the human placenta hCG
is preferentially secreted from the microvillous surface of
syncytial trophoblast [36]. It has been argued that LH as an
efficient pregnancy-establishing signal to the corpus luteum
evolved in primates with the haemochorial condition [37]. In
murid rodents the trophoblast giant cells which are essentially
situated in maternal blood are the source of prolactins [38].
Despite the obvious advantages of the haemochorial
arrangement, it has several disadvantages. There is the
possibility of extensive bleeding at parturition. There is a
greater chance of passage of cells between organisms, especially
from the fetus to the maternal organism resulting in such
phenomena as microchimerism or more acute situations such
as erythroblastosis fetalis [39–41]. The villous haemochorial
condition appears morphologically particularly vulnerable to
such exchanges. This tendency somewhat counteracts the
advantage immunologically of having maternal cells in their
inactivated circulating form and the absence of more direct
access to maternal connective tissue with its repertoire of
immunoactivators [42]. Nevertheless the human and great apes
appear to be at the upper limits of size and length of gestation
for haemochorial placentae.
In species that rapidly tap maternal vessels, another potential disadvantage is the possibility of too much oxygen for good
embryonic development. Oxidative stress may be alleviated by
physiological means such as elevated thioredoxin levels [43,44]
and other molecules with antioxidant properties [45]. This
disadvantage is also limited in a number of other ways.
Relatively slow development of the chorioallantoic placenta
and especially its circulation is common. For example in rats
Enders and Carter: Comparative Placental Structure
and mice the chorioallantoic placenta does not develop until
nearly half way through the gestation period. The initial
association with maternal blood is in the yolk sac placenta and
is formed by decidual cell modifications that lead to trophoblast spaces within the parietal trophoblast [46]. When the
ectoplacental cone reaches the mesometrial chamber the
remodeled chamber is filled with maternal blood from the
surrounding sinusoidal venules [47]. In many species of
bats the definitive haemochorial placenta is preceded by an
endotheliochorial placenta. In species such as primates in
which trophoblast taps maternal blood quickly the conceptus is
initially poorly oxygenated [48,49], and the initial maternal
blood flow in the forming placenta is probably both sluggish
and at low pressure [50]. In the armadillo the maternal vessels
that are invaded by the developing villi are endometrial venous
sinuses [51].
Endotheliochorial placentae
The advantages of the endotheliochorial placenta are less
obvious. The presence of a maternal endothelium presumably
reduces the incidence of passage of fetal cells into the maternal
organism. In many species with this type of placenta the
maternal capillaries grow into the trophoblast without most of
the cellular elements that are ordinarily found in endometrial
connective tissue. The induction of elongated anastomotic
sinusoidal capillary beds allows for an orderly pathway into the
resulting placental labyrinth [52]. The labyrinth has large
amounts of trophoblast in contact with an interstitial membrane and at places with the maternal endothelium. However,
neither dendritic cells nor extravasated B and T lymphocytes
are normally present in the labyrinth. The function of
the highly modified endothelial cells is more problematic.
Especially strange is the situation in some of the shrews in
which the trophoblast layer becomes much reduced and highly
fenestrated [53,54]. The endotheliochorial type of placenta is
found in some very large animals such as the elephant with its
large size and long gestation [55].
Epitheliochorial placentae
The epitheliochorial type of arrangement has as its advantage
the safety factor of the isolation of fetal and maternal
components. The presence of two complete epithelia should
diminish both immunological problems as well as the deportation of fetal cells to the maternal organism. Indeed the largest
mammals with long gestation periods, the whales, have this
type of placenta. The disadvantage of the greater difficulty in
passage of materials between organisms is partially overcome
by a variety of mechanisms. In the horse, secreted eCG passes
readily into the maternal vascular system because of the
migration of trophoblastic girdle cells into the endometrium to
form endometrial cups. The resultant proximity of these cells
to maternal capillaries and invasion into maternal lymphatics
S7
facilitates CG passage to the mare [56–58]. In the cow as
an example of a synepitheliochorial placenta, the fusion of
binucleate trophoblast cells with maternal epithelial cells facilitates passage of prolactin to the maternal organism [59].
Passive immunity on the other hand is normally passed to the
neonate via colostrum rather than prior to parturition.
COUNTERCURRENT BLOOD FLOW
There is a strong tendency for placentae to form countercurrent blood flow systems within the interhaemal areas. Since
the maternal and fetal blood vessels normally enter interhaemal
areas from different directions, there is a tendency for general
counterflow. However, when we examine the microvasculature
the problem increases in complexity. Dantzer et al. [60]
elucidate some of the problems with classification of blood
flow as crosscurrent or countercurrent at the level of the
capillaries or blood spaces. The relationships can also vary with
gestational age as in the change from a simple series of capillary
loops in early gestation in the cow to a more elaborately
branched exchange area but more of a crosscurrent in later
gestation [61]. One might think that the endotheliochorial
placenta would produce a countercurrent arrangement, but the
multiple branching anastomotic network shown beautifully in
the corrosion casts of the mink placenta for example results in
a crosscurrent at the microvessel level [62]. Physiological
studies also tend to show varying degrees of crosscurrent
exchanges [63]. With haemochorial placentae it might be
thought that there would be less tendency for countercurrent
situations. However, in a great many species the maternal
blood enters the labyrinth in trophoblast-lined channels that
direct the arterial flow to the fetal side of the labyrinth before
the blood enters thin parallel channels which return maternal
blood to veins in the basal plate. Whereas usually the path of
the fetal blood is not as straight and therefore less rigorously
countercurrent with branching occurring at various levels in
the labyrinth, there is nevertheless a region near the chorionic
plate where fine fetal capillaries are parallel to the maternal
channels that are most richly oxygenated. Such an arrangement has been reported for the rabbit and caviomorph rodents,
and on anatomical grounds the arrangement is similar in the
tenrec and the elephant shrew.
The advantage of countercurrent over various crosscurrent
flow patterns is greatest for highly diffusible molecules such as
oxygen or carbon dioxide. Even then, the difference in transfer
efficiency tends to disappear when the diffusing capacity of the
placenta is low in relation to blood transport capacity [64]. In
other words, when oxygen transfer is flow-limited, the vascular
geometry assumes greater importance. Placental diffusing
capacity is greater by several orders of magnitude in the
haemochorial placentae of rodents and lagomorphs, which have
a predominantly countercurrent arrangement, than in the
epitheliochorial placenta of the sheep, which has a largely
crosscurrent arrangement of blood vessels [65].
S8
In addition to the interhaemal areas and other areas not
associated with maternal-fetal exchanges, there is often a
spongy zone formed by a meshwork of trophoblastic channels
but free of the fetal vessels or connective tissue that are present
in the labyrinth. This arrangement places trophoblast cells in
contact with maternal blood without increasing the interhaemal distance and may also tend to reduce the possibility of
cells of fetal origin and embolisms entering the blood stream.
This type of arrangement is found in many species irrespective
of the number of trophoblast layers, whether the trophoblast is
cellular or syncytial, and in such diverse species as the
hedgehog tenrec [16] and the capybara [66], as well as
laboratory rodents.
CONCLUSIONS
Study of comparative placentation is a humbling experience.
Even keeping track of the definitive type of placenta in the
known examples of over 100 families of the 19 or 20 orders of
Eutherian mammals is a difficult task. More significantly, the
lack of substantial electron microscopic studies of the placentae
Placenta (2004), Vol. 25, Supplement A, Trophoblast Research, Vol. 18
of many families and the lack of studies of the way in which the
definitive placentae form limit our attempts to generalize. The
absence of fossil evidence of placental structure in species
thought to be ancestral adds to the difficulty in determining
what aspects of placentation are primitive or derived features.
Although placentation is only indirectly related to the environment (for example animals that must be actively mobile at
birth have a longer gestation), clearly the placenta is of extreme
importance in survival of the species. Animals with less
efficient placentae would be expected to be eliminated rapidly,
especially in small mammals whose populations must bloom
when food is available. It has recently been estimated that in a
single fish genus (Poeciliopsis) it has taken 750 000 years or less
to evolve a placenta [67]. Eomaia, one of the best preserved
primitive Eutherian mammal fossils, is considered to be 125
million years old [68]. It is therefore probable that in all
modern mammals many aspects of placental development
are derivative and cannot really be considered primitive.
However, more complete studies of divergent types of mammalian placentae would certainly help our understanding of
mammalian interrelationships.
ACKNOWLEDGEMENTS
It is a pleasure to acknowledge Diana Mossman and Paula Holahan for making available material from the Mossman Collection at the University of Wisconsin
Zoological Museum. We also wish to thank Graham Burton for access to and assistance with the Boyd Collection at Cambridge University, and Heinz Kunzle for
continued provision of tenrec materials. The blocks of elephant placenta were graciously provided by Twink Allen and Peter Wooding.
REFERENCES
[1] Monkley SJ, Delaney SJ, Pennisi DJ, Christiansen JH, Wainwright BJ.
Targeted disruption of the Wnt2 gene results in placentation defects.
Development 1996;122:3343–53.
[2] Rossant J, Cross JC. Placental development: lessons from mouse mutants.
Nat Rev Genet 2001;2:538–48.
[3] Cross JC, Baczyk D, Dobric N, Hemberger M, Hughes M, Simmons
DG et al. Genes, development and evolution of the placenta. Placenta
2003;24:123–30.
[4] Carrington JC, Ambros V. Role of microRNAs in plant and animal
development. Science 2003;301:336–8.
[5] Takamoto N, Zhau B, Tsai SY, DeMayo FJ. Identification of Indian
hedgehog as a progesterone-responsive gene in the murine uterus. Mol
Endocrinol 2002;16:2338–48.
[6] Wooding FBP, Flint APF. Placentation. In: Lamming GE, editor.
Marshall’s Physiology of Reproduction, Part I. London: Chapman and
Hall; 1994;III:233–460.
[7] Leiser R, Pfarrer C, Abd-Elnaeim M, Dantzer V. Feto-maternal anchorage in epitheliochorial and endotheliochorial placental types studied by
histology and microvascular corrosion casts. Trophoblast Res 1998;
12:21–39.
[8] Mess A. Evolutionary transformations of chorioallantoic placental characters in rodentia with special reference to hystricognath species. J Exp
Zool Part B 2003;299:78–98.
[9] Enders AC, Blankenship TN, Lantz KC, Enders SS. Morphological
variation in the interhemal areas of chorioallantoic placentae. Trophoblast
Res 1998;12:1–19.
[10] Roberts RM, Bazer FW. The functions of uterine secretions. J Reprod
Fert 1988;82:878–92.
[11] McDowell K, Sharp DC, Zavy MT, Fazleabas A, Roberts RM, Bazer
FW. Partial characterization of the equine uteroferrin-like protein. J
Reprod Fert 1982;32(Suppl):329–34.
[12] King BF. The fine structure of the placenta and chorionic vesicles of the
bush baby, Galago crassicaudata. Am J Anat 1984;169:101–16.
[13] Burton GJ. Review Article. Placental uptake of maternal erythrocytes: a
comparative study. Placenta 1982;3:407–33.
[14] Mossman HW. Vertebrate Fetal Membranes. New Brunswick (NJ):
Rutgers Univ Press, 1987.
[15] King BF, Tibbitts FD. The ultrastructure of the placental labyrinth in
the kangaroo rat, Dipodomys. Anat Rec 1969;163:543–54.
[16] Carter AM, Blankenship TN, Kunzle K, Enders AC. Structure of the
definitive placenta of the tenrec, Echinops telfairi. Placenta 2004;25:
218–232.
[17] Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR. Identification
and localization of divalent metal transporter-1 (DMT-1) in term human
placenta. Placenta 2000;21:799–804.
[18] King BF. Comparative studies of structure and function in mammalian
placentas with special reference to maternal-fetal transfer of iron. Am
Zool 1992;32:331–42.
[19] King BF, Hastings RA. The comparative fine structure of the interhemal
membrane of chorioallantoic placentas from six genera of myomorph
rodents. Am J Anat 1977;149:165–80.
[20] Prasad MR, Mossman HW, Scott GL. Morphogenesis of the fetal
membranes of an American mole, Scalopus aquaticus. Am J Anat 1979;
155:31–68.
[21] Malassine A, Leiser R. Morphogenesis and fine structure of the nearterm placenta of Talpa europaea: I. Endotheliochorial labyrinth. Placenta
1984;5:145–58.
[22] Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O’Brien SJ.
Molecular phylogenetics and the origins of placental mammals. Nature
2001;409:614–8.
[23] Carter AM. Evolution of the placenta and fetal membranes seen in the
light of molecular phylogenetics. Placenta 2001;22:800–7.
[24] Luckett WP. Uses and limitations of mammalian fetal membranes and
placenta for phylogenetic reconstruction. J Exp Zool 1993;266:514–27.
[25] King BF, Enders AC. Comparative development of the mammalian yolk
sac. In: Nogales FF, editor. The human yolk sac and yolk sac tumors.
Berlin: Springer-Verlag; 1993, p. 1–23.
[26] Enders AC, King BF. Formation and differentiation of extraembryonic
mesoderm in the rhesus monkey. Am J Anat 1988;181:327–40.
[27] Bianchi DW, Wilkins-Haug LE, Enders AC, Hay ED. The origin
of extraembryonic mesoderm in experimental animals: relevance to
chorionic mosaicism in humans. Am J Med Genet 1993;46:542–50.
Enders and Carter: Comparative Placental Structure
[28] Karim KB, Wimsatt WA, Enders AC, Gopalakrishna A. Electron
microscopic observations on the yolk-sac of the Indian fruit bat, Rousettus
leschenaulti (Desmarest) (Pteropidae). Anat Rec 1979;195:493–509.
[29] Gulbis B, Jauniaux E, Cotton F, Sordeur P. Protein and enzyme patterns
in the fluid cavities of the first trimester gestational sac: relevance to the
absorptive role of secondary yolk sac. Mol Hum Reprod 1998;4:857–62.
[30] Takata K, Hirano H. Mechanism of glucose transport across the human
and rat placental barrier: a review. Microsc Res Tech 1997;38:145–52.
[31] Battaglia FC, Regnault TRH. Placental transport and metabolism of
amino acids. Placenta 2001;22:145–61.
[32] Cariappa R, Heath-Monnig E, Smith CH. Isoforms of amino acid
transporters in placental syncytiotrophoblast: plasma membrane localization and potential role in maternal/fetal transport. Placenta 2003;
24:713–26.
[33] Stulc J. Placental transfer of inorganic ions and water. Physiol Rev 1997;
77:805–36.
[34] Kristoffersen EK, Matre R. Co-localization of the neonatal Fc gamma
receptor and IgG in human placental term syncytiotrophoblasts. Eur J
Immunol 1996;26:1668–71.
[35] Leitner K, Ellinger A, Zimmer KP, Ellinger I, Fuchs R. Localization of
beta 2-microglobulin in the term villous syncytiotrophoblast. Histochem
Cell Biol 2002;117:187–93.
[36] Jablonka-Shariff A, Garcia-Campayo V, Boime I. Evolution of lutropin to
chorionic gonadotropin generates a specific routing signal for apical
release in vivo. J Biol Chem 2002;277:879–82.
[37] Maston GA, Ruvolo M. Chorionic gonadotropin has a recent origin
within primates and an evolutionary history of selection. Mol Biol Evol
2002;19:320–35.
[38] Soares MJ, Faria TN, Hamlin GP, Lu X-J, Deb S. Trophoblast cell
differentiation: expression of the placental prolactin family. In: Soares
MJ, Handwerger S, Talamantes F, editors. Trophoblast cells—pathways
for maternal-embryonic communication. New York: Springer-Verlag;
1993, p. 45–67.
[39] Benirschke K, Kaufmann P. Pathology of the Human Placenta. 2nd ed
New York: Springer-Verlag, 1990.
[40] Bianchi DW, Lo YM. Fetomaternal cellular and plasma DNA trafficking:
the Yin and Yang. Ann N Y Acad Sci 2001;945:119–21.
[41] Nelson JL. Microchimerism in human health and disease. Autoimmunity
2003;36:5–9.
[42] Hunt JS, Petroff MG, Burnett TG. Uterine leukocytes: key players in
pregnancy. Semin Cell Dev Biol 2000;11:127–37.
[43] Perkins A, Di Trapani G, McKay M. Immunocytochemical localization
of thioredoxin in human trophoblast and decidua. Placenta 1995;
16:635–42.
[44] Lopata A, Sibson MC, Enders AC, Bloomfield KL, Gregory MS, Di
Trapani G et al. Expression and localisation of thioredoxin during early
implantation in the marmoset monkey. Mol Hum Reprod 2001;
7:1159–65.
[45] Jauniaux E, Gulbis B, Burton GJ. The human first trimester gestational
sac limits rather than facilitates oxygen transfer to the foetus—a review.
Trophoblast Res 2003;17:S86–93.
[46] Welsh AO, Enders AC. Trophoblast-decidual cell interactions and
establishment of maternal blood circulation in the parietal yolk sac
placenta of the rat. Anat Rec 1987;217:203–19.
[47] Welsh AO, Enders AC. Chorioallantoic placenta formation in the rat: II.
Angiogenesis and maternal blood circulation in the mesometrial region of
the implantation chamber prior to placenta formation. Am J Anat 1991;
192:347–65.
[48] Huston J, Schaaps JP. Echographic and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy. Am J Obstet
Gynecol 1987;157:162–8.
S9
[49] Burton GJ, Jauniaux E. Maternal vascularisation of the human placenta:
does the embryo develop in a hypoxic environment? Gynecol Obstet
Fertil 2001;29:503–8.
[50] Blankenship TN, Enders AC. Modification of uterine vasculature during
pregnancy in macaques. Microsc Res Tech 2003;60:390–401.
[51] Enders AC, Welsh AO. Structural interactions of trophoblast and uterus
during hemochorial placenta formation. J Exp Zool 1993;266:578–87.
[52] Pfarrer C, Winther H, Leiser R, Dantzer V. The development of the
endotheliochorial mink placenta: light microscopy and scanning electron
microscopical morphometry of maternal vascular casts. Anat Embryol
1999;199:63–74.
[53] Wimsatt WA, Enders AC, Mossman HW. A re-examination of the
chorioallantoic placental membrane of a shrew, Blarina brevicauda:
resolution of a controversy. Am J Anat 1973;138:207–33.
[54] Kiso Y, Yasufuku K, Matsuda H, Yamauchi S. Existence of an
endothelio-endothelial placenta in the insectivore, Suncus murinus. Cell
Tissue Res 1990;262:195–7.
[55] Allen WR, Mathias S, Wooding FBP, van Aarde RJ. Placentation in the
African elephant (Loxodonta africana): II Morphological changes in the
uterus and placenta throughout gestation. Placenta 2003;24:598–617.
[56] Allen WR. Immunological aspects of the equine endometrial cup reaction
and the effect of xenogeneic pregnancy in horses and donkeys. J Reprod
Fert 1982;31(Suppl):57–94.
[57] Enders AC, Liu IKM. Trophoblast-uterine interactions during equine
chorionic girdle cell maturation, migration and transformation. Am J
Anat 1991;192:366–81.
[58] Enders AC, Lantz KC, Schlafke S, Liu IKM. New cells and old vessels:
the remodeling of the endometrial vasculature during establishment of
endometrial cups, in: Equine reproduction VI, Biol Reprod, Mono Ser
1995;1:181–190.
[59] Wooding FBP. The synepitheliochorial placenta of ruminants: binucleate
cell fusions and hormone production. Placenta 1992;13:101–13.
[60] Dantzer V, Leiser R, Kaufmann P, Luckhardt M. Comparative morphological aspects of placental vascularization. Trophoblast Res 1988;
3:235–60.
[61] Pfarrer C, Ebert B, Miglino MA, Klisch K, Leiser R. The threedimensional feto-maternal vascular interrelationship during early bovine
placental development: a scanning electron microscopical study. J Anat
2001;198:591–602.
[62] Krebs C, Winther H, Dantzer V, Leiser R. Vascular interrelationships of
near-term mink placenta: light microscopy combined with scanning
electron microscopy of corrosion casts. Microsc Res Tech 1997;
38:125–36.
[63] Faber JJ, Thornburg KL. Placental physiology: structure and function of
fetomaternal exchange. New York: Raven Press, 1983.
[64] Metcalfe J, Bartels H, Moll W. Gas exchange in the pregnant uterus.
Physiol Rev 1967;47:782–838.
[65] Longo LD. Respiratory gas exchange in the placenta. Handbook of
Physiology, Section 3, The Respiratory System, Volume IV, Gas
ExchangeBethesda: Am Physiol Soc; 1987, p. 351–401.
[66] Miglino MA, Carter AM, dos Santos Ferraz RH, Fernandes Machado
MR. Placentation in the capybara (Hydrochaerus hydrochaeris), agouti
(Dasyprocta aguti) and paca (Agouti paca). Placenta 2002;23:416–28.
[67] Reznick DN, Mateos M, Springer MS. Independent origins and rapid
evolution of the placenta in the fish genus Poeciliopsis. Science 2002;
298:1018–20.
[68] Weil A. Mammalian evolution: upwards and onwards. Nature 2002;
416:798–9.