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Nutritional Influences on Implantation and Placental Development

Article  in  Nutrition Reviews · June 2006

DOI: 10.1301/nr.may.S12-S18 · Source: PubMed

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James C Cross Lindsay Anderson

The University of Calgary Government of British Columbia, Canada


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Nutritional Influences on Implantation and Placental

James C. Cross, DVM, PhD, and Lindsay Mickelson, BSc

The placenta is critical for nourishing the fetus connect to the umbilical cord1,2; b) promoting blood flow
throughout pregnancy, and also produces hormones to the implantation site and intervillous space by produc-
that alter the metabolic functions of the mother. While ing angiogenic factors and promoting vasodilation3; 3)
the effects of nutrition on fetal development and long- producing metabolic hormones such as placental lacto-
term outcome have been very well documented, there gens and placental growth hormone,4,5 which alter insu-
are only a few reports based on studies in rat, sheep, lin production and promote insulin resistance in maternal
and guinea pigs on how specific nutrients or general tissues to increase glucose availability to the fetus, as
nutritional status affect the development of the blas-
well as leptin6 and ghrelin7; 4) accumulating glycogen in
tocyst, its implantation, and the subsequent placenta.
times of glucose surplus8 (Figure 1).
The data suggest that placental development is highly
adaptable and that many types of compensation are Each of these placental functions is highly regu-
possible for suboptimal nutrition. lated and undertaken by a specific compartment of the
placenta. The barrier covering the chorionic villi in the
Key words: amino acids, development, glucose, pla-
human and rodent placenta is composed of several cell
centa, trophoblast
© 2006 International Life Sciences Institute
layers, including a multinucleated syncytium of tro-
doi: 10.1301/nr.may.S12–S18 phoblast (syncytiotrophoblast) cells.2 Nutrient trans-
porters are highly expressed to facilitate and regulate
the transfer between the maternal and fetal circulatory
INTRODUCTION systems. A specialized subtype of trophoblast cell
invades outside of the confines of the villi (these cells
As mammals, the placenta is something that we are called extravillous cytotrophoblasts in humans and
can’t do without during our embryonic and fetal lives, trophoblast giant cells in rodents) to encounter uterine
but which we soon forget about after birth. Even for spiral arteries. They replace the endothelial cell lining
clinicians and researchers who are interested in under- of the arteries and therefore lead to the transition into
standing complications in fetal growth, the placenta is the trophoblast-lined blood vessels (hemochorial).3
often either not included in the analysis or is given The different placental hormones are produced by the
cursory examination—such as by simply weighing it. invasive trophoblast and the syncytiotrophoblast cells.
This treatment is unjustified, as the placenta is not simply Finally, glycogen accumulates in both villous and
a selective filter for nutrient transport to the growing extravillous trophoblast cells, but is most dramatic in
fetus. Rather, it plays several key roles in most mamma- the rodent placenta in cells designated as glycogen
lian species in regulating the nutritional status of both the trophoblast cells.8 They first start to appear in the
fetus and the mother by: a) forming a highly branched latter part of gestation within the middle layer of
villous structure that forms the surface area for nutrient placenta called the spongiotrophoblast (often also
and gas exchange and establishes its own circulation to called the junctional zone), which is analogous to the
cytotrophoblast columns in the human placenta. After
Dr. Cross and Ms. Mickelson are with the Genes appearing, they subsequently invade diffusely into the
and Development Research Group, University of Cal- interstitium of the decidual tissue of the uterus.
gary, Calgary, Alberta, Canada. The purpose of this review is to discuss the role of
Please address all correspondence to: Dr. James nutrition in regulating these developmental events. Al-
Cross, Genes and Development Research Group, Of-
though there is only limited direct experimental evi-
fice Room 2279 Health Sciences Centre, 3330 Hospi-
tal Drive NW, Calgary, Alberta Canada T2N 4N1; dence, it is clear that some specific nutrients and general
Phone: 403-220-6876; Fax: 403-270-0737; E-mail: nutritional status can play key roles in altering the de-
jcross@ucalgary.ca. velopmental trajectory of the placenta, effects that have

S12 Nutrition Reviews姞, Vol. 64, No. 5

Figure 1. Structures and essential functions of the human placenta.

direct consequences for the survival of the fetus and the elsewhere,2,8 but some of the key molecular pathways
well-being of the newborn. regulating placental development are summarized in Fig-
ure 2.
MOLECULAR MECHANISMS OF PLACENTAL There are several important themes that emerge
DEVELOPMENT from the work to date. First, the placenta normally
achieves the delicate balance of having the correct pro-
The cellular and molecular mechanisms underlying portions of the different cell types to achieve its func-
the development of the placenta are best understood in tions. Second, differentiation of the trophoblast compart-
the mouse as a result of studies of experimental embry- ments of the placenta is regulated by largely independent
ology, the ability to culture trophoblast stem cells, and molecular mechanisms (Figure 2). Third, primary defects
analysis of several mouse mutants that have defects in in one developmental process can lead to secondary
placental development usually resulting in embryonic changes in other parts. For example, as is observed in
mortality or intrauterine growth restriction. Whereas we retinoblastoma (Rb) mutant placentas, failure to properly
knew of only a few genes essential for placental devel- form villi can lead to secondary attempts to hypervascu-
opment a decade ago,9 we now know of approximately larize the villi that do form.10 This suggests that devel-
100. These subjects have been recently reviewed in detail opment is adaptable to environmental circumstances.

Figure 2. Developmental origins and molecular mechanisms underlying the differentiation of trophoblast cell types in the mouse

Nutrition Reviews姞, Vol. 64, No. 5 S13

Indeed, the differentiation potential of trophoblast cells is EFFECT OF MATERNAL NUTRITIONAL
highly regulated by oxygen levels.11-13 Given this, it STATUS ON VILLOUS PLACENTAL
stands to reason that nutrients and nutritional status may DEVELOPMENT
also have similar effects.
While specific nutrients have not been evaluated for
effects on post-implantation placental development, the
EFFECT OF GLUCOSE, AMINO ACIDS, AND effect of feed restriction and overfeeding have been
FASTING ON BLASTOCYST DEVELOPMENT evaluated in rat, sheep, and guinea pig models. Curi-
ously, at a general level, while the responses in rats and
The progenitors of the placenta are established in the
sheep are similar, the guinea pig appears to show a
pre-implantation embryo. Many years of culturing mam-
different effect. In rats, protein restriction from the time
malian embryos have led to a significant understanding
of mating leads to intrauterine growth restriction (IUGR)
of their metabolism and of the optimal medium for
of approximately 10%, but the placentas show enhanced
embryos that allows them to reach the blastocyst stage
villous development.23 While the overall volume of the
and to successfully implant if transferred into a recipient
villous placenta (called the labyrinth in rodents) is not
mother.14 Blastocyst development and subsequent im- changed, the villous surface area is enhanced by about
plantation potential are reduced in diabetic mothers,15 15%, implying that branching had become more elabo-
and this effect can be mimicked by culturing embryos in rate. The underlying molecular mechanism is unclear.
high concentrations of D-glucose.16,17 Amino acid sup- Interestingly, though, the underlying vasculature does
plementation also affects development. Essential amino not undergo a proportional expansion. This implies that
acid supplementation during in vitro culture of pre- the trophoblast cells alter their development, perhaps in
implantation embryos enhances post-implantation fetal an attempt to compensate for the protein restriction.
development.14 In addition, a strong beneficial effect of IUGR may have occurred because the response was
nonessential amino acid supplementation is observed in inadequate or because, in the absence of a proportional
mouse embryos, leading to enhanced blastocyst forma- increase in vascularization, the uptake efficiency of the
tion18 and increased implantation rates.14,18 placenta may not have been sufficient.
The beneficial effect of the nonessential amino acids The effect of overall energy restriction on placental
can be observed in an in vitro model of implantation development and structure in rats has not been docu-
called blastocyst attachment and outgrowth. In the ab- mented, and this is significant since it is obviously
sence of amino acids, blastocysts do not attach but enter unclear if the ability of the placenta to compensate (or
a state of quiescence analogous to delayed implanta- what type of compensation occurs) is dependent on the
tion.19 With the addition of amino acids, the trophoblast specific type of nutrient deprivation. Maternal iron re-
cells change their adhesive characteristics and form out- striction before and during pregnancy also leads to an
growths. The effect is mediated by the mTOR signaling increase in villous surface area but, again, with a failure
system and can therefore be inhibited with rapamycin.19 in vascular adaptation.24 This model leads to anemia, and
Interestingly, blastocysts can be exposed to the attach- the response indicates that trophoblast-branching mor-
ment-promoting amino acid levels for as little as a phogenesis and differentiation can be regulated by tissue
critical 8-hour period. This narrow window implies that oxygenation. This is consistent with previous findings
amino acid sensing by blastocysts is a checkpoint mech- with knockout mice lacking hypoxia-inducible factor
anism for determining whether to continue to develop. If (HIF).11 Most other animal models of IUGR use feed
the blastocyst does not initiate attachment to the uterus, restriction rather than protein restriction.
the maternal-side window of implantation will close and In sheep, overall caloric intake has been tested as a
pregnancy will not be established. model and, interestingly, both feed restriction and over-
Another potential mechanism by which undernutri- feeding can lead to IUGR.25-28 The placenta in sheep is
tion may affect blastocyst development has recently been distributed over about 100 separate cotyledons, and nu-
suggested. Ghrelin is a hormone first described for its trient status can affect both the number of cotyledons that
ability to increase fat deposition by stimulating appetite form and their subsequent size and vascularity. Tropho-
and decreasing fat utilization.20 Its expression is stimu- blast proliferation25 and the expression of angiogenic
lated by fasting and insulin-induced hypoglycemia.20 factors27,28 are reduced by overfeeding during the first
The ghrelin receptor is also expressed by pre-implanta- and second trimesters, leading to smaller cotyledons that
tion embryos, and ghrelin treatment significantly reduces are relatively poorly vascularized. By focusing on shorter
the number of inner cell mass and trophectoderm cells in intervals, Wallace et al.26 have been able to show that
blastocysts,21 similar to the effect of a low-protein diet cotyledon number is most affected by overnourishment
during the period of blastocyst formation.22 during the first trimester, whereas final cotyledon size is

S14 Nutrition Reviews姞, Vol. 64, No. 5

most affected by nutritional status in the second and third needs to be expanded to leptin expression and particu-
trimesters. This coincides with the fact that cotyledons larly to the glucose transporters GLUT1 and GLUT3,
are formed during the first trimester, and implies that since both increases and decreases in their expression
once the number is established, the placenta has only a have been reported.37,38 However, in a food restriction
limited ability to compensate through increasing the size model of IUGR in rats, GLUT expression levels did not
of the remaining cotyledons. correlate with endogenous glucocorticoid levels, perhaps
In guinea pigs, a feed restriction model has been suggesting that glucocorticoids may not directly regulate
widely used as a model of IUGR. In this model, pregnant GLUT expression.43
dams are fed only 50% to 70% of the normal ad libidum
intake and birth weights are reduced by about 30%. By
term, the labyrinth layer of placenta is reduced in overall MODULATION OF PLACENTAL HORMONE
size,29,30 and the villous surface area is also dramatically PRODUCTION BY MATERNAL NUTRIENT
reduced.30 The response of the placental structure is
significantly different than that in the rat models dis-
The placenta produces a number of metabolically
cussed above. It is not clear whether this reflects a
important hormones. The placenta in many mammalian
species difference, differences in response to protein
species has been reported to produce placental-specific
only versus total diet restriction, or is due to the fact that
members of the prolactin/growth hormone superfamily.
the guinea pig model involves a more significant chal-
lenge to the pregnancy. Insulin-like growth factor (IGF) In humans, both placental lactogen44 and placental
I and II expression, and the ratio of the IGFs to IGF- growth hormone45,46 are produced. In rodents, a placen-
binding proteins is reduced in the guinea pig model.31-34 tal growth hormone is not made but a huge cluster of
Moreover, IGF levels appear to be correlated with the over 25 prolactin-related genes that have been amplified
extent of villous branching in the labyrinth and are during evolution are expressed in the placenta, largely by
inversely correlated with the trophoblast barrier thick- trophoblast giant cells.47 The functions of most of the
ness.32,33 These observations are interesting, because prolactin-related genes are unknown. Four placental lac-
IGF-II mutant mice have defects in the extent of villous togen I (PL-I)-related proteins and a single PL-II all
branching in the labyrinth and the barrier thickness is work through the prolactin receptor,4 and as such can
increased.35,36 potentially mediate several important maternal adapta-
tions to pregnancy that are attributed to prolactin.48
These include mammary development and lactogenesis,
EFFECT OF GLUCOCORTICOIDS ON pancreatic islet hyperplasia and the associated increase in
insulin production, as well as insulin resistance. There is
very little information about what regulates the synthesis
In rats, glucocorticoid treatment of pregnant dams
and release of the PLs. PL-I expression is suppressed by
during the second half of gestation results in IUGR. The
expression of several hormone and nutrient transporter progesterone.49 PL-II expression is reduced by IL-6,50
genes has been reported to be altered in this model.37-41 and has been found to be expressed in a circadian
Notably, though, placental weight is also dramatically rhythm.51 PL-II is suppressed by melatonin, which is
smaller in this model, and the decrease in placental size also expressed in the placenta.51
is associated with an increase in apoptotic cell death41 The placenta also produces leptin52 and ghrelin,20
that occurs in both the labyrinth and junctional zone, hormones that suppress and stimulate appetite, respec-
though the specific cell type(s) have not be defined.42 tively, and regulate other metabolic processes as
Therefore, the data on gene expression should be inter- well.6,20,53 While they no doubt contribute to metabolic
preted with caution, since it is not clear if the changes control during pregnancy, there are few insights into the
simply reflect a change in cell composition or a physio- specific function of the placentally derived hormones.
logical change in expression. Ain et al.41 have addressed Leptin is expressed by syncytiotrophoblast cells under
the point by conducting a microarray experiment focused the control of the Gcm1 transcription factor.6,39,54,55
on the family of prolactin-related hormone genes, and Leptin receptors are also expressed in the placenta,
then performing in situ hybridization to determine the suggesting an autocrine or negative feedback func-
relative number and spatial patterns of expressing cells. tion.39,40 Ghrelin expression in the placenta has only
It is evident from this work that at least some of the gene recently been described, but the site of the expression has
expression changes induced by glucocorticoids, includ- not been identified. Interestingly, while fasting leads to
ing the placental lactogens and IGF-II, are physiological increased levels of ghrelin in circulation during preg-
and due to cellular expression levels rather than to the nancy,56 placental expression is not altered by fasting in
pathological loss of cell types. This type of work clearly pregnant rats.7

Nutrition Reviews姞, Vol. 64, No. 5 S15

PLACENTAL DEPOSITS OF GLYCOGEN culature in the placenta. Mol Cell Endocrinol. 2002;
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S18 Nutrition Reviews姞, Vol. 64, No. 5

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