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Biological features of placental programming


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The placenta is a key organ in programming the fetus for later disease. This review outlines eight of many structural and physiological features of the placenta which are associated with adult onset chronic disease. 1) Placental efficiency relates the placental mass to the fetal mass. Ratios at the extremes are related to cardiovascular disease risk later in life. 2) Placental shape predicts a large number of disease outcomes in adults but the regulators of placental shape are not known. 3) Non-human primate studies suggest that at about mid-gestation, the placenta becomes less plastic and less able to compensate for pathological stresses. 4) Recent studies suggest that lipids have an important role in regulating placental metabolism and thus the future health of offspring. 5) Placental inflammation affects nutrient transport to the fetus and programs for later disease. 6) Placental insufficiency leads to inadequate fetal growth and elevated risks for later life disease. 7) Maternal height, fat and muscle mass are important in combination with placental size and shape in predicting adult disease. 8) The placenta makes a host of hormones that influence fetal growth and are related to offspring disease. Unfortunately, our knowledge of placental growth and function lags far behind that of other organs. An investment in understanding placental growth and function will yield enormous benefits to human health because it is a key player in the origins of the most expensive and deadly chronic diseases that humans face.
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Biological Features of Placental Programming
Kent L. Thornburg1,2,3,4,6, Kevin Kolahi1,2, Melinda Pierce5, Amy Valent4, Rachel Drake1,
and Samantha Louey1,6
1Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, USA
2Department of Biomedical Engineering, Oregon Health and Science University, Portland,
Oregon, USA
3Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA
4Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon, USA
5Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA
6Moore Institute for Nutrition and Wellness, Oregon Health and Science University, Portland,
Oregon, USA
The placenta is a key organ in programming the fetus for later disease. This review outlines eight
of many structural and physiological features of the placenta which are associated with adult onset
chronic disease. 1) Placental efficiency relates the placental mass to the fetal mass. Ratios at the
extremes are related to cardiovascular disease risk later in life. 2) Placental shape predicts a large
number of disease outcomes in adults but the regulators of placental shape are not known. 3) Non-
human primate studies suggest that at about mid-gestation, the placenta becomes less plastic and
less able to compensate for pathological stresses. 4) Recent studies suggest that lipids have an
important role in regulating placental metabolism and thus the future health of offspring. 5)
Placental inflammation affects nutrient transport to the fetus and programs for later disease. 6)
Placental insufficiency leads to inadequate fetal growth and elevated risks for later life disease. 7)
Maternal height, fat and muscle mass are important in combination with placental size and shape
in predicting adult disease. 8) The placenta makes a host of hormones that influence fetal growth
and are related to offspring disease. Unfortunately, our knowledge of placental growth and
function lags far behind that of other organs. An investment in understanding placental growth and
function will yield enormous benefits to human health because it is a key player in the origins of
the most expensive and deadly chronic diseases that humans face.
One of the most important findings gleaned from recent epidemiological research across the
globe is that placental phenotype predicts post-natal disease in offspring. Scientist have long
known that the fetus depends on the placenta to acquire its nutrients for growth. For the past
Corresponding author: Kent L. Thornburg, Professor of Medicine, Center for Developmental Health, Knight Cardiovascular Institute,
Oregon Health & Science University, 3303 SW Bond Ave, Portland, OR, USA, 97239,
HHS Public Access
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Published in final edited form as:
. 2016 December ; 48(Suppl 1): S47–S53. doi:10.1016/j.placenta.2016.10.012.
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twenty-five years it has been recognized that fetal growth itself is an independent predictor
of adult-onset disease. Since the placenta regulates the flow of nutrients from the mother to
the fetus, most placental biologists assume that it must also play a role in determining
disease risk in the adult life of the offspring.
There is ever-increasing evidence that the host of biological mechanisms that regulate
placental growth and development also serves as causative agents for programming of
chronic disease[1]. This article introduces eight out of many placental features that are
associated with the programming of the fetus for later disease and outlines remaining gaps in
knowledge regarding the links between epidemiological associations and their biological
1) Placental Size and Efficiency
There are a number of adult disease conditions that are associated with placental size such as
heart failure[2] and hypertension[3]. However, placental size and mass are crude measures
of function, hence additional insight into the efficacy of overall placental function can be
learned by comparing placental weight to fetal weight. Thus, various combinations of
placental and fetal growth patterns offer insight into the developmental mechanisms that lead
to disease in later life well beyond the predictive value of either birthweight or placental
weight alone. Consequently, the concept of “efficiency” of the placenta has become useful.
Efficiency is defined as the ratio of placental weight to fetal weight at any given stage of
gestation, but is usually applied at term [4]. By custom, Europeans tend to use the placental
weight to fetal weight ratio to define efficiency whereas North Americans more often use the
inverse. So if the placenta is 15% of the fetal weight, the fetus is therefore 6.7 times heavier
than the placenta. Either way, efficiency indicates how much fetal mass has accumulated for
every gram of placenta. For example, if two 3,000 gram term babies are born with placentas
that weigh 450 grams and 900 grams respectively, the former placenta is deemed twice as
efficient as the latter.
While the concept of efficiency has become a useful tool for biologists who study fetal
programming it should be stated up front that it does not much insight into the regulation of
placental or fetal growth. However, it does provide a measure of integrated placental
function over gestation. Several studies have linked placental efficiency to disease outcomes
in offspring. Martyn et al [5], showed that among men in Sheffield, UK, placental weight
expressed as a percentage of fetal weight produces a “U” shaped curve. Figure 1 shows that
the highest risks for coronary heart disease were found in pregnancies characterized by
placentas that were less than 15% of birthweight, or were greater than 22% of the fetal
weight [5]. Thus, both high efficiencies, at the 15% end of the scale, and low efficiencies at
the 22% end of the scale, were associated with elevated risks for heart related deaths.
The use of proxy markers of efficiency is also helpful, such as the ratio of a dimension or
area of the delivered placenta to fetal weight. For example, the area of the delivered placenta
as a percentage of birthweight was associated with a 2.5 fold risk for sudden cardiac death
among women in the Helsinki Birth Cohort but not in men [6].
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The concept of placental efficiency is an artificial construct which is influenced by complex
biological factors that directly affect placental mass and underlie the transport function
required for fetal growth. Nevertheless, placental efficiency is at best a crude marker of the
environmental conditions in which a population of pregnant women was exposed. Recent
data demonstrate that average placental efficiency within a population can change across
time. In one Saudi population, the average placental weight increased by 120g in less than
10 years without a change in the average birthweight of ~3.25 kg [7]. Thus, on a population
basis, the average placenta became less efficient for this group over a single decade.
The changing efficiency suggests that the growth patterns of placentas in a given population
can be altered by the surrounding nutritional environment and perhaps other unknown
biological factors that could affect women in the population. Other features of the
environment such as shifts in the constituent microorganisms that constitute the maternal
microbiome, might also play a role. Such variations in the maternal microbiome could also
reflect dietary changes [8]. This aspect of placental biology needs further investigation. The
determinants of placental efficiency will remain in the realm of speculation until the
biological mechanisms that determine placental growth and related transport functions are
found. This was nicely shown in a published discussion of fetal growth regulation [9].
Placental efficiency is also interesting in light of differences in growth strategies between
male and female fetuses. Males tend to invest less in placental mass for the degree of fetal
weight at birth and thus have more efficient placentas than do females who invest more in
placental tissue for a given mass of fetus that accumulates at term [10, 11].
2) Placental Shape
If a placenta is not perfectly round at delivery, it can be described via its longest axis and a
perpendicular short axis. These two axes, length and width, were measured on all delivered
placentas in Helsinki hospitals for half a century and similar measurements were also
recorded in The Netherlands, India and Saudi Arabia. These records now allow us to relate
placental size and shape to fetal growth and disease conditions among adults (Table 1).
Although length and width generally correlate as expected [16], what is unexpected is that
often one dimension, but not the other is associated with a particular disease outcome or
condition. The specificity associated with the predictive value of disease provided by only a
single placental axis has been previously reviewed [17] [18], but a few examples will suffice
to make the point. In Riyadh, Saudi Arabia, the width of the delivered term placenta but not
its length was associated with offspring birthweight and head circumference [16]. This effect
was observed most strongly in short mothers. Birth weight increased by 125 g for every cm
increase in placental width (95% confidence interval 88 – 162, p < 0.001), but only by 20 g
per cm increase in each cm of placental length (95% CI, 13 to 53, p = 0.2). Thus placental
growth in one placental dimension was more highly associated with fetal growth than the
other. Similarly, in babies born to mothers in Helsinki who had preeclampsia, it was the
width of the placenta, but not its length that was most highly associated with the severity of
the disease [12]. In a separate study, short placental length but not width was associated with
lifespan in 1200 men in the Helsinki Birth Cohort [19]. Changes in placental shape may also
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occur following a severe reduction in placental capacity; this is discussed in more detail in
the “Placental Plasticity” section below based on studies in the non-human primate.
The differing biological roles of length and width in the placenta remain unexplained. If the
placenta begins as a perfectly round structure, there is no length or width, just a single
diameter. One would also expect that the placental axes would grow together and at the same
rate so that the placenta would maintain a round shape over the whole of the gestational
period. However, among some 6,000 deliveries, the average dimension of placentas in the
Helsinki Birth Cohort was about 2.6 ± SD 2.0 cm longer than wide (range, 0–21 cm)
(unpublished). Because differences in dimension appear to have biological meaning, many
questions arise. Are the growth rates of the axes independently regulated? If so, what are the
biological mechanisms that drive growth in different directions and why is an asymmetrical
placenta more likely to predict disparate factors like the rate of fetal growth, male lifespan
and offspring disease? These questions are ripe for study.
Finding strategies to study the regulation of placental shape is not easy. However, we offer
two suggestions for low hanging fruit. 1) Serial measurements of placental size, shape and
mass across the whole of gestation. This can be done in a non-invasive study using state of
the art ultrasonography. 2) There are animal models where nutritional or restriction of blood
flow patterns are associated with changes in shape. Using such models, we should be able to
determine the temporal and spatial features that are associated with asymmetrical growth of
the placenta. See the discussion of placental shape in the non-human primate study below.
3) Placental Plasticity
The degree to which the placenta is able to alter its growth trajectory according to the
availability of nutrients has not been well studied. However, it has long been known that
farmers have learned to vary the nutrition of ewes in order to deliver larger lambs at birth
[20]. Farmers would reduce the nutrient intake of previously well-fed ewes in the first few
weeks of pregnancy by placing the pregnant sheep on poor pasture to stimulate rapid
placental growth and expansion of its vasculature. When returned to a lush pasture, the fetus
would then grow to a larger size with the support from its newly enlarged placenta. There
are parallels in the human.
Several species of non-human primates have two implantation sites that give rise to primary
and secondary placental lobes that are connected by bridge vessels [21]; this arrangement
occurs rarely in humans too. The accommodation of the primary lobe following functional
loss of the secondary lobe following ligation of the bridge vessels provides clues to growth
responses and limitations of placental adaptation. The responses to ligation of the bridge
vessels has been studied in the rhesus monkey at 80 days (0.47 gestation) and at 110 days
(0.67 gestation), where term is 167 days [22]. In these studies, near term fetal growth was
nearly normal in the early ligation group but reduced in the older 110 day group, thus
demonstrating early but not late gestation plasticity. In the early ligation group, the
functional primary lobe was, on average, heavier and thicker than controls, having grown
nearly twice as fast as normal in response to ligation. The rapid growth of the lobe was
associated with a change in the length to width ratio compared to control or late ligation
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lobes (1.25 vs. 1.08). Compensatory growth was, thus, more rapid in one direction than the
Ligation at 0.67 gestation produced a very different primary lobe compared to lobes of
control unligated placentas or late ligation placentas. In the late gestation ligation group,
primary lobes grew at only half the normal rate, indicating a greatly diminished adaptive
growth and not surprisingly, fetal growth was negatively impacted. These experiments
demonstrate the obvious: fetal growth depends on an adequate placenta. But more
importantly, the experiments demonstrate that the primate placenta loses its capacity for
robust compensatory growth at some point early in the second half of gestation. The data
further show that the shape of the placenta can be modified by changes in nutrient
availability, supporting the idea that changes in shape within a specific population is
influenced by the nutrition environment. The ligation experiments suggest that failure to
mount a robust response to external insults can lead to placental insufficiency and fetal
4) Integration of Placental Signaling and Lipid Transport
A key function of the placenta is to transport maternal nutrients to the fetus, a function that
can be dramatically altered through changes in signaling pathways. One might assume that
signaling conditions which lead to suppression of transport systems would have detrimental
effects on fetal growth and alter lifelong disease risks. The interactions among pathways
within the placenta are known to respond to changing environments including maternal
obesity, maternal nutrient delivery to the placenta, maternal cortisol levels and hypoxia.
Studies by Jansson and colleagues [23] are examples of investigations into signaling
pathway interactions that integrate the actions of several systems. Unfortunately, there are
few studies that pursue this purpose in the placenta.
The interplay between signaling systems is important, highly complex and beyond the scope
of this review. Over the past two decades, tremendous progress has been made in
understanding the regulation of glucose and amino acid transport. These have been recently
reviewed [24–27]. However, one class of molecule in the signaling field is just now
receiving adequate attention: lipid molecules. Recent data show that maternal lipid profiles
are important as determinants of fetal growth and thus as programming agents [28]. Lipids
affect placental metabolism and are required for normal fetal growth. Deficits in supply of
long chain polyunsaturated fatty acids (LCPUFA) due to an inadequate diet have
pronounced detrimental effects on the maturing fetal organ systems. The brain and
cardiovascular systems especially require substantial amounts of maternally acquired
LCPUFA in late gestation for normal development [29, 30]. For the cardiovascular system, a
deficient perinatal supply of LCPUFAs leads to hypertension in the adult [31, 32]. Thus, the
developing fetal brain and cardiovascular systems depend heavily on the placental supply of
LCPUFAs and omega-3-PUFAs.
In addition to their necessity for normal fetal development, fatty acids are critical for normal
placental function. Fatty acids and LCPUFA in particular, are potent stimulators of the
retinoid X receptor (RXR) and peroxisome proliferator activated receptor (PPAR) nuclear
pathways [33, 34], two pathways that are indispensable for normal placentation and
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trophoblast function [35]. LCPUFA influence the antioxidant capacity of the placenta via
nuclear factor erythroid type 2 (NRF2 / NF-E2), a master regulator of antioxidant gene
expression. Roles for LCPUFA in anti-inflammatory pathways include direct stimulation of
mediators produced via COX2 [36, 37] and being ligands for GPR120 which suppresses
inflammation [38]. These additional roles also have implications for fetal development
especially in pregnancies complicated by oxidative stress, inflammation and gestational
diabetes [39–41]. Maternal supplementation with LCPUFA has beneficial effects [42], but
may not ameliorate poor fetal outcomes in high-risk pregnancies [43], suggesting these
outcomes are due to dysfunctions placental transport rather than disruptions in maternal
supplies. Low fetal LCPUFA levels will likely become more common as the prevalence of
maternal obesity and diabetes continues to rise [44]. The role of placental lipoprotein lipases
in releasing fatty acids has been nicely documented [45] and an interaction between
unsaturated fatty acids and amino acid transport has been clearly demonstrated [46].
However, the exact mechanisms by which lipids are transported and stored have yet to be
determined. Data from our laboratory suggest that the cytotrophoblast is as important as the
syncytiotrophoblast in regulating lipid storage [47]. Thus, there may be many additional
lipid based signaling pathways within the tissues of the placenta that are yet to be
5) Placental Inflammation
Placental inflammation can arise from several causes. The most well-known is in response to
an invading infectious agent. In addition, it is becoming increasingly evident that abnormal
maternal metabolic status can stimulate inflammatory processes in the placenta without an
infectious agent being present. Radaelli et al., showed that among the 400 plus gene
transcripts modified in women with insulin dependent glucose control in the 3rd trimester,
stress-activated and inflammatory response genes represented some 18% of regulated genes
[48]. Interleukins, leptin, and tumor necrosis factor-alpha receptors were upregulated and
their downstream molecular adaptors were prominently changed. Changes in genes
regulating extracellular matrix components and angiogenic processes underlie structural
reorganization of the placenta in diabetic women. In a comparison study, Enquobahrie et al.,
reported similar trends but with additional pathways and clusters that suggest a host of
changes that go beyond inflammation [49]. These studies illustrate the high degree to which
maternal metabolic disease is influential in determining placental form and function.
Women with low muscle mass, who themselves often had low birthweight, have low rates of
protein turn-over [50, 51] and abnormal placental amino acid transport properties [51]. In
addition, thinness in pregnant women is associated with a pro-inflammatory gene expression
pattern with increased levels of interferon gamma and associated pathways but not with
granulocyte or monocyte infiltration [52]. Thus, such placentas are not inflamed using the
classical definition of “hot” inflammation that is characterized by immune cell infiltration. It
appears that the field of placentology would benefit from new definitions of inflammation
that would indicate the various levels of inflammatory responses that represent different
physiological, pathological and gene expression states. The need to recognize different
presentations of inflammation has been at least superficially addressed in the field of cancer
[53]. We speculate that when placentas have “smoldering” inflammation, various fetal
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functions are affected that lead to fetal programming and enduring pro-inflammatory
processes that last well into postnatal life. Figure 2 illustrates how hypothetical increases in
inflammation and oxidative stressors in the womb could work in tandem to cause lifelong
pro-inflammatory states in the fetus. The field of placentology is ripe for new, broadly
agreed upon definitions of inflammation based not only on histological markers but gene
expression patterns as well.
6) Placental Insufficiency
Placental vascular insufficiency can stem from an anatomically inadequate placenta, poor
vascular development, or chronically decreased uterine or umbilical blood flow, all of which
lead to inadequate oxygen and substrate flow to the fetus. The negative consequences of
placental insufficiency are multifactorial and include, but are not limited to diminished
substrate delivery leading to fetal growth restriction. Increased oxidative stress, increased
cytokine production and associated inflammation, altered endocrine status and changes in
epigenetic signaling may further compound the long term programming effects of placental
insufficiency. The importance of robust placental blood flow and a functional vasculature in
animal models of placental insufficiency are reviewed elsewhere [54, 55]. Decreased
umbilical artery blood flow velocity is associated with smaller terminal villi [56] and
reduced trophoblast and capillary volumes [57] which contribute to decreased nutrient
supply to the fetus. In the face of decreased nutrient supply, the fetus will curb growth and
redistribute cardiac output; even those organs thought to be somewhat “protected” may still
be compromised and make other adaptations [58–60]. For more vulnerable organs such as
the kidney, liver and pancreas, the programming effects of placental insufficiency on
nephron number, hypertension, and metabolic disease have been well documented [61–66].
Yet, there are basic questions that remain unanswered. Under what circumstances do the
vascular elements of the placenta fail to grow and expand as gestation proceeds? What are
the processes that lead to the appropriate microvascular development required to maintain
the low resistance status of the placenta? Is it possible to stimulate new growth in
undergrown placentas to reverse the condition of placental insufficiency?
7) Maternal Phenotype
While birthweight remains a reliable indicator of fetal growth and future disease risk,
additional associations with adult-onset disease have been discovered. Among people in the
Helsinki Birth Cohort, phenotypic features reflecting maternal body composition in
combination with placental phenotypic features are now known to be important predictors of
long term disease risk. This is especially true for cardiovascular disease. The primary causes
of cardiac death include coronary artery occlusion (myocardial infarction), heart failure and
sudden cardiac death (ventricular fibrillation). In each case, placental phenotype is related to
the risk for the condition. However, the predictive value of the placenta is further enhanced
by knowing more about the body type of the mother. Particularly important are maternal
body mass index, height alone or pelvic dimensions.
Three combinations of placental/maternal phenotype predict coronary disease among men,
but not women in the Helsinki Birth Cohort. In all three, a low ponderal index of the
newborn predicted the disease. One maternal-placental combination was in women who
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were below the median in height and two were in women above the median height with
either a high or low body mass index. In the short women, the hazard ratio for coronary heart
disease was 1.14 (95% confidence interval, C.I. 1.08–1.21, p=0.0001) for each cm difference
in the length and width. In the tall women with a high body mass index, the ratio was 1.25
(C.I. 1.10–1.42, p=0.0007) per 40 cm2 decrease in surface area. In the tall mothers with a
BMI that was below the median, the ratio was 1.07 (C.I. 1.02–1.13, p=0.01) per 1% increase
in the placental weight/birthweight ratio. Interestingly, coronary heart disease in women was
not predicted by placental growth in this cohort. In first born women only, a 1kg increase in
birthweight was associated with a 25% lower risk for coronary disease (HR 0.75 C.I. 0.60–
0.93, p=0.008).
In the Helsinki Birth Cohort, heart failure was associated with a small placental surface area.
In people born to mothers of below median height and a placental area less than 225 cm2,
the odds ratio for chronic heart failure was 2.3 (1.2–4.2, p=0.05), compared with people
born with a placental area greater than 295 cm2. In the same cohort, sudden cardiac death
was associated a thin placenta, the only known disease association with placental thinness.
The hazard ratio was 1.47 (C.I. 1.11–1.93, p=0.006) for each g/cm2 decrease in thickness.
These findings raise interesting questions. Does a woman’s body type affect the form and
function of the placenta or do placentas of a particular phenotype affect maternal physiology
in a specific way? At present, we know little about the determinants of placental growth and
its interaction with the maternal body. This gap in knowledge presents an important
opportunity for clever new approaches to placental biology.
8) Placental Hormone Production
Placental production of growth hormone (GH-V), human chorionic somatomammotropin
(CSH), corticotropin-releasing hormone (pCRH), 11β-hydroxysteroid dehydrogenase type II
(11β-HSD2) and thyroid hormone are all important for maintaining a normal pregnancy and
supporting normal fetal growth. However, the degree to which these hormones cause
programming effects in the offspring has not been well studied. Herein we suggest that
IGF-1, glucocorticoids and thyroid hormone are linked to fetal growth and long term
IGF1 and IGF2 are both important as growth factors in fetal and placental development.
Both are synthesized in macrophages and endothelial cells throughout gestation (Hien et al.,
J Anat. 2009 Jul; 215(1): 60–68). The fetus relies on insulin-dependent IGF-1 secretion,
which ensures a direct linkage between nutrient availability and growth [67]. This is in
contrast to infants who switch to GH regulation to reach their adult growth potential.
Maternal under- and over-nutrition result in obesity in adult offspring coexisting with
hyperinsulinemia even after postnatal catch-up growth. IGF-I is an important regulator of
growth and the somatotropic axis is significantly dysregulated by maternal malnutrition [68].
Treatment with IGF-I postnatally has been shown to decrease systolic blood pressures,
insulin concentrations and retroperitoneal fat pads in fetal growth restricted (FGR) offspring
[69]. Additionally, GH sensitivity is decreased in FGR offspring, further supporting that fetal
growth and programming are associated with the anabolic actions of GH in response to a
poor postnatal nutritional environment [70].
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The IGF2 gene strongly influences placental growth; under conditions where placental size
is reduced, such as fetal growth restriction, its placental expression is also reduced [71]. If
IGF2 is deleted from fetal and placental tissues the mouse placenta has a reduced
labyrinthine nutrient exchange area and a loss of glycogen cells in the junctional zone [72].
The H19 gene normally silences the IGF2 gene. When the H19 gene is deleted, the IGF2
gene is upregulated stimulating a selective increase in the labyrinthine zone which allows a
greater area for nutrient exchange[72, 73]. The changes in placental growth related to
changes in IGF2 gene expression are reflected in nutrient flux to the fetus and thus, fetal
Epigenetic modification of the glucocorticoid system has been shown to be developmentally
sensitive in several organ systems. Human studies have shown that elevated prenatal stress
correlates with abnormal fetal brain development [74]. Glucocorticoids are required for
tissue maturation and organ development, especially in lungs and heart. However, FGR as
well as subsequent cardiovascular and metabolic alterations in the adult life can occur with
supra-physiologic levels of glucocorticoids [75, 76]. Since cortisol is known to inhibit fetal
growth, the placenta protects the fetus from exposure to even normal maternal levels of
cortisol. To maintain lower physiologic levels of fetal cortisol, placental 11β-HSD2 acts to
buffer these negative effects of cortisol by catalyzing reactions to promote the inactive 11-
keto forms. 11β-HSD2 is expressed in cytotrophoblasts during the first trimester and in
syncytiotrophoblast as gestation progresses [77]. Placental expression and activity of 11β-
HSD2 are decreased in FGR, fetal hypoxia, chorioamnionitis, and maternal protein
restriction [78]. Glucocorticoids have long been shown to be a major programming agent for
adult disease. The placenta plays an integral role in coordinating both placental and maternal
metabolic processes as well as optimizing the nutritional needs of a growing fetus, which all
influence the downstream lifelong health consequences. However, the regulation of these
processes and glucocorticoid systems within the placenta are still incompletely understood.
Maternal thyroid disease including both hyper- and hypothyroidism are associated with poor
pregnancy outcomes such as FGR, preterm birth, and pre-eclampsia [79]. Thyroid hormone
(TH) has long been known to be essential for normal fetal brain development and thus,
severe maternal hypothyroidism from iodine deficiency is the most common preventable
cause of mental retardation around the world [80, 81]. Studies in fetal sheep show TH also
has a critical role in the maturation of the myocardium, decreasing cardiomyocyte
endowment both when there is too much, or too little TH [82]. TH promotes secretion of
placental hormones critical for pregnancy maintenance as early as implantation [83] and
cytotrophoblast cells are responsive to TH by increasing syncytialization rate, thereby
stimulating secretion of factors that promote placenta integrity [84, 85]. Despite the obvious
role of TH in placental function, little is known about placental TH signaling at a cellular
level. Given the known relationship between obesity and thyroid hormone status [86] and
increasing rates of maternal obesity, it is imperative to understand placental thyroid signaling
under both normal and obesogenic conditions.
The clear cut effects of these hormones on fetal and placental growth strongly suggest a role
in fetal programming. However, except for IGF-1, cortisol and thyroid hormone, little is
known about the role of other hormones in determining the long term health of offspring;
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both those produced by the placenta and those produced by the mother or fetus but who have
actions on the placenta. The role of placental hormones in programming is one of the most
neglected areas of research in reproductive biology.
The placenta is a key organ in programming the fetus for later disease. In recent years many
aspects of placental phenotype and function are associated with adult-onset disease. It is now
appropriate to consider several late onset diseases to be placental diseases because the
associations are so powerful. The discovery that placental shape interacts with maternal
body composition as predictors of later disease is especially profound and provides a sense
of urgency for our efforts in understanding the biological factors that underlie the
associations. There is a need for young scientists to develop high levels of expertise in this
field at a cellular, but also at a systems level to fully appreciate the maternal-placental-fetal
interactions. Without profound progress in the field, the origins of the chronic diseases that
cause the highest rates of mortality worldwide will not be understood.
The authors thank Lisa Rhuman and Kim Rogers for their excellent office assistance.
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Figure 1.
The risk of coronary heart disease based on the weight ratio of placenta and fetus. [5]
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Figure 2.
The primary elements that lead to a pro-inflammatory state in both fetal and postnatal life.
Beginning left, pro-inflammatory molecules affect placental inflammatory gene expression
depending on the physiological status of the mother. A pro-inflammatory placenta leads to
compromised immune function in the fetus along with elevated levels of oxidative stress.
The outcome is a fetus that suffers “smoldering, cold inflammation” that may persist and
make it more likely that the offspring will be more vulnerable for adult-onset chronic
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Author Manuscript Author Manuscript Author Manuscript Author Manuscript
Thornburg et al. Page 17
Table 1
Diseases and their relationship to placental phenotype
Stroke placenta pathology; narrow placenta in preeclampsia)[5, 12]
Hypertension placenta size and shape[3]
Hypertension small placentas[3]
Metabolic Disease/Obesity placenta surface area; U shaped risk[13]
Coronary Heart Disease placenta size and shape, maternal phenotype[14]
Heart Failure small placenta, short mother[2]
Sudden Cardiac Death thin placenta (men); large placenta (women)[6]
Asthma short length, placental dimensions[15]
. Author manuscript; available in PMC 2017 December 01.
... A eficiência placentária é uma variável descrita como um índice capaz de refletir a capacidade uterina de produzir animais, com a tendência de aumentar conforme a ordem de parição das matrizes, prolificidade e programação fetal (Özyürek e Türkyilmaz, 2020). De acordo com Thornburg et al. (2016) a eficiência placentária retrata a capacidade que a placenta possui em transferir os nutrientes necessários para o crescimento fetal. ...
Full-text available
O objetivo deste estudo foi verificar os efeitos da eficiência placentária de cabras e caracterizar sua influência sobre a sobrevivência e desempenho de cabritos até a fase de desmame. Para isso, foi criado um modelo de regressão múltipla para identificação de quais características influenciam, e em qual proporção, o peso dos cabritos ao desmame. No intuito de verificar quais características afetavam a chance de sobrevivência dos cabritos até o desmame, elaborou-se um modelo linear generalizado. Para serem incluídas nos modelos, as variáveis precisavam ser significantes ao nível de 5% de probabilidade (P-valor < 0,05). As variáveis estatisticamente significativas e mantidas no modelo final para determinar o peso ao desmame das crias, foram eficiência placentária, peso da mãe ao parto e quantidade de crias. A eficiência placentária aumentou em 0,0582 o peso ao desmame dos cabritos, enquanto um quilo a mais ao parto das matrizes ocasionou aumento de 0,2310 kg na mesma variável. A cada cabrito a mais nascido por parto, aumentou-se em 7,0066 kg o peso ao desmame. A eficiência placentária diminuiu o risco de sobrevivência das crias em 0,01%. Em contrapartida, o peso da matriz ao parto e quantidade de crias nascidas aumentaram em 0,44% e 71,89% a chance de sobrevivência dos cabritos até o desmame. É indicado que, para obtenção de maior produtividade no sistema, sejam atendidas as exigências nutricionais dos animais em todos os seus estágios fisiológicos, visto que uma nutrição inadequada consegue limitar o desempenho dos animais.
... The placenta plays a critical role during pregnancy by maintaining pregnancy, nurturing the fetus and mediating bidirectional communication between the mother and the fetus. More importantly, the placenta is a key mediator of fetal programming by which the long term health and disease risk of offspring is predisposed by the in utero environment such as nutrition, inflammation, endocrine status [1][2][3]. Placental functions require a high demand of energy. Thus, the placenta is an active metabolic tissue, accounting for 40 percent of oxygen consumption [4] and one third of glucose uptake by the placental-fetal unit during late pregnancy [5]. ...
Introduction: Accumulating evidence suggests that mitochondrial structural and functional defects are present in human placentas affected by pregnancy related disorders, but mitophagy pathways in human trophoblast cells/placental tissues have not been investigated. Methods: In this study, we investigated three major mitophagy pathways mediated by PRKN, FUNDC1, and BNIP3/BNIP3L in response to AMPK activation by AICAR and knockdown of PRKAA1/2 (AKD) in human trophoblast cell line BeWo and the effect of AKD on mitochondrial membrane potential and ATP production. Results: Autophagy flux assay demonstrated that AMPK signaling activation stimulates autophagy, evidenced increased LC3II and SQSTM1 protein abundance in the whole cell lysates and mitochondrial fractions, and mitophagy flux assay demonstrated that the activation of AMPK signaling stimulates mitophagy via PRKN and FUNDC1 mediated but not BNIP3/BNIP3L mediated pathways. The stimulatory regulation of AMPK signaling on mitophagy was confirmed by AKD which reduced the abundance of LC3II, SQSTM1, PRKN, and FUNDC1 proteins, but increased the abundance of BNIP3/BNIP3L proteins. Coincidently, AKD resulted in elevated mitochondrial membrane potential and reduced mitochondrial ATP production, compared to control BeWo cells. Conclusions: In summary, AMPK signaling stimulates mitophagy in human trophoblast cells via PRKN and FUNDC1 mediated mitophagy pathways and AMPK regulated mitophagy contributes to the maintenance of mitochondrial membrane potential and mitochondrial ATP production.
... Furthermore, different placental cell types display their own unique expression profiles, which may differ from that of the aggregate placental tissue (Pique-Regi et al., 2019). Expression changes are also observed in placental pathologies (Nishizawa et al., 2011), which may cause long-term repercussions on the health of both affected mothers and fetuses, including higher predisposition to cardiovascular, respiratory, metabolic and psychiatric diseases (Thornburg et al., 2016). Early placental functioning has also been likened to that of cancer progression (Costanzo et al., 2018). ...
Full-text available
The placenta is a vital organ formed during pregnancy, and being the interface between the mother and fetus, it is paramount that placental functioning is strictly controlled. Gene expression in the placenta is finely tuned—with aberrant expression causing placental pathologies and inducing stress on both mother and fetus. Gene regulation is brought upon by several mechanisms, and small non-coding RNAs (sncRNAs) have recently been appreciated for their contribution in gene repression. Their dysregulation has been implicated in a range of somatic and inherited disorders, highlighting their importance in maintaining healthy organ function. Their specific roles within the placenta, however, are not well understood, and require further exploration. To this end, we summarize the mechanisms of microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), and transfer RNAs (tRNAs), their known contributions to human placental health and disease, the relevance of sncRNAs as promising biomarkers throughout pregnancy, and the current challenges faced by placental sncRNA studies.
... Human placenta is a key organ in "programming the fetus for later disease" (3), and, as a consequence, it might be even more important in programming newborn disease. ...
Full-text available
Purpose We aimed to clarify and contribute to a better comprehension of associations and correlations between placental histological findings, pregnancy evolution, and neonatal outcomes. Study Design This is a longitudinal and prospective observational study, performed between May 2015 and May 2019, on 506 pregnant women. Clinical data related to pregnancy outcome, neonatal health status, and placental histology were primarily collected. Twin pregnancies or malformed newborns were excluded and therefore the study was conducted on 439 cases. These cases have been then subdivided into the following study groups: (a) 282 placentas from pathological pregnancies; and, (b) a control group of 157 pregnancies over 33 weeks of gestational age, defined as physiological or normal pregnancies due to the absence of maternal, fetal, and early neonatal pathologies, most of which had undergone elective cesarean section for maternal or fetal indication. Results A normal placenta was present in 57.5% of normal pregnancies and in 42.5% of pathological pregnancies. In contrast, placental pathology was present in 26.2% of normal pregnancies and 73.8% of pathological pregnancies. Comparison of the neonatal health status with the pregnancy outcome showed that, among the 191 newborns classified as normal, 98 (51.3%) were born from a normal pregnancy, while 93 (48.7%) were born from mothers with a pathological pregnancy. Among the 248 pathological infants, 59 (23.8%) were born from a mother with a normal pregnancy, while 189 (76.2%) were born from pregnancies defined as pathological. Conclusion Placental histology must be better understood in the context of natural history of disease. Retrospective awareness of placental damage is useful in prevention in successive pregnancy, but their early identification in the evolving pregnancy could help in association with biological markers or more sophisticated instruments for early diagnosis.
... Placental dysfunction continues to be a leading cause of perinatal morbidity and mortality, including fetal growth restriction (FGR), pre-eclampsia, and stillbirth [1][2][3][4][5][6][7]. Even in infants who survive the perinatal period, impaired placental function is strongly associated with the development of future chronic diseases [1,2,8,9]. ...
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Objective The aim of this study was to determine in utero fetal-placental growth patterns using in vivo three-dimensional (3D) quantitative magnetic resonance imaging (qMRI). Study design Healthy women with singleton pregnancies underwent fetal MRI to measure fetal body, placenta, and amniotic space volumes. The fetal-placental ratio (FPR) was derived using 3D fetal body and placental volumes (PV). Descriptive statistics were used to describe the association of each measurement with increasing gestational age (GA) at MRI. Results Fifty-eight (58) women underwent fetal MRI between 16 and 38 completed weeks gestation (mean = 28.12 ± 6.33). PV and FPR varied linearly with GA at MRI (rPV,GA = 0.83, rFPR,GA = 0.89, p value < 0.001). Fetal volume varied non-linearly with GA (p value < 0.01). Conclusions We describe in-utero growth trajectories of fetal-placental volumes in healthy pregnancies using qMRI. Understanding healthy in utero development can establish normative benchmarks where departures from normal may identify early in utero placental failure prior to the onset of fetal harm.
For a long time it was assumed that the risk for diseases such as coronary heart disease (CHD) or insulin resistance, for example, develops from the genetic potential of the parents and is amplified by environmental influences such as an unfavorable lifestyle. This view has been completely overturned in the last two decades by the concept of fetal programming. The concept implies that a stimulus or insult during a sensitive period of fetal development produces permanent changes in structure, physiology, and metabolism, determining later risk for chronic diseases such as CHD and insulin resistance, as well as allergies, an impaired stress response, and many others in adulthood. The concept of Fetal Origins of Adult Disease (FOAD) was introduced by the British epidemiologist David Barker more than 20 years ago and has been the subject of intensive research ever since. The current research approaches aim to identify the biological mechanisms by which a prenatal stimulus or insult alters fetal development, the time lag between prenatal stimulus/insult and later disease, and the multiple factors that contribute to disease risk throughout the lifespan.
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Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally driven gene expression in placenta function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm epigenetic signatures, the placenta transcriptome and cellular composition. C57BL6/J males were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 enrichment at imprinted genes, and at promoters of genes involved in metabolism and development. Notably, sperm altered H3K4me3 was localized at placental enhancers and genes implicated in placental development and function. Bulk RNA-sequencing on placentas detected paternal obesity-induced sex-specific changes in gene expression associated with hypoxic processes such as angiogenesis, nutrient transport and imprinted genes. Paternal obesity was also linked to placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity-effects on placenta development and function as one mechanism underlying offspring metabolic disease. Summary sentence Paternal obesity impacts the sperm epigenome at genes implicated in placenta development and is associated with an altered placenta transcriptome and trophoblast cell lineage specification.
It is well understood that exposure to particulate matter (PM) can have adverse effects on the nervous system. When pregnant women are exposed to PM, their fetuses are also affected through the placenta. However, the mechanisms by which fetal brain development is regulated between mother and fetus remain unclear. C57BL/6 J pregnant mice were exposed to PM at embryonic day (E) 2.5, 5.5, 8.5, 11.5, 14.5, and 17.5 via nasal drip at three doses (3, 6, 12 mg/kg of body weight) or PBS control. Neurobehavioral changes in the offspring were examined at 5-6-week-old by open field test (OFT) and elevated plus maze (EPM). The maternal and fetal brain and placenta were collected at E18.5, and molecular signal changes were explored using transcriptome analysis. We found that both male and female low-dose pups and male middle-dose pups traveled a significantly longer distance than controls in EPM tests. Both male and female low-dose pups showed a higher frequency of entering the center area and female low-dose pups exhibited a higher percentage of distance moved in the center area than controls in OFT tests. Gene expression in the maternal brain, fetal brain, and placenta at E18.5 was altered. Differentially expressed genes were enriched in the neuroactive ligand-receptor interaction pathway in all three tissue types. Pathway analysis revealed that the PI3K-Akt and PKC signaling was dysregulated in the fetal brain in the high-dose group compared with the control group. The pathways play a role in neuronal survival and apoptosis. Furthermore, there is a dose-dependent increase in Caspase-6, neuronal apoptosis and neurodegeneration biomarker, levels in E18.5 fetal brain (P = 0.06). In conclusion, our study demonstrated that prenatal PM exposure enhanced exploration and locomotor activity in adolescent offspring and altered molecular events in maternal brain, fetal brain, and placenta. The connections of these changes warrant further investigations.
Maternal lipid metabolism status during pregnancy may have pivotal effects on a healthy pregnancy, the progression of labor, and childbirth. Based on evidence, changes in maternal lipid profile and metabolism is related to various alterations in fetal metabolic status, fat mass, birth weight and can result in serious maternal and fetal complications. 15-lipoxygenase accounts as a key enzyme in metabolizing polyunsaturated fatty acids that generate various inflammatory lipid metabolites. The possible involvement of 15- lipoxygenase and its metabolites in the inflammatory process, cell proliferation and death, and immune response has been postulated. The indicative role of the 15- lipoxygenase enzymatic pathway in the implantation process, stages of pregnancy, embryogenesis, organogenesis, progression of labor, pregnancy period, and pregnancy-associated complications is remarkable. Accordingly, this study will review the research conducted on the role of 15- lipoxygenase in different reproductive tissues, and its pathological role in pregnancy-related diseases to provide more insight regarding the emerging role of 15-lipoxygenase in normal pregnancy.
Studies have shown that the maternal nutrition during critical periods of development not only influences fetal growth but also plays a significant role in determining the risk of chronic disease in later life through developmental ‘programming’. The placenta acts as a tool for ‘programming’ as it has the ability to adapt according to the maternal environment. There are morphological adaptations and also alterations in the expression of genes as a consequence of placental adaptations; which are critical for both placental and fetal development. Maternal nutrients especially the micronutrients (folate, vitamin B12) of the one carbon cycle and long chain polyunsaturated fatty acids (LCPUFA) are essential for placental and fetal growth and development. They are interconnected through the one carbon cycle and play a critical role in determining pregnancy outcome. A disturbed one carbon cycle leads to altered methylation of genes which play an important role in placental development and fetal growth. This review discusses the role of maternal one carbon metabolites and its influence on placental ‘programming’ and long term health.
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While the human placenta must provide selected long-chain fatty acids to support the developing fetal brain, little is known about the mechanisms underlying the transport process. We tracked the movement of the fluorescently labeled long-chain fatty acid analogue, BODIPY-C12, across the cell layers of living explants of human term placenta. Although all layers took up the fatty acid, rapid esterification of long-chain fatty acids and incorporation into lipid droplets was exclusive to the inner layer cytotrophoblast cells rather than the expected outer syncytiotrophoblast layer. Cytotrophoblast is a progenitor cell layer previously relegated to a repair role. As isolated cytotrophoblasts differentiated into syncytialized cells in culture, they weakened their lipid processing capacity. Syncytializing cells suppress previously active genes that regulate fatty-acid uptake (SLC27A2/FATP2, FABP4, ACSL5) and lipid metabolism (GPAT3, LPCAT3). We speculate that cytotrophoblast performs a previously unrecognized role in regulating placental fatty acid uptake and metabolism.
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Over the past quarter century it has become clear that adult onset chronic diseases like heart disease and type 2 diabetes have their roots in early development. The report by David Barker and colleagues showing an inverse relationship between birthweight and mortality from ischemic heart disease was the first clear-cut demonstration of fetal programming. Because fetal growth depends upon the placental capacity to transport nutrients from maternal blood, it has been a suspected causative agent since the original Barker reports. Epidemiological studies have shown that placental size and shape have powerful associations with offspring disease. More recent studies have shown that maternal phenotypic characteristics, such as body mass index and height, interact with placental size and shape to predict disease with much more precision than does birthweight alone. For example, among people in the Helsinki Birth Cohort, who were born during 1924–1944, the risk for acquiring colorectal cancer increased as the placental surface became longer and more oval. Among people in whom the difference between the length and breadth of the surface exceeded 6 cm, the hazard ratio for the cancer was 2.3 (95% CI 1.2–4.7, p=0.003) compared with those in whom there was no difference. Among Finnish men, the hazard ratio for coronary heart disease was 1.07 (1.02–1.13, P =0.01) per 1% increase in the placental weight/birthweight ratio. Thus, it appears that the ratio of birthweight to placental weight, known as placental efficiency, predicts cardiovascular risk as well. Babies born with placentas at the extremes of efficiency are more vulnerable for adult onset chronic diseases. Recent evidence suggests that placental growth patterns are sex specific. Boys’ placentas are, in general, more efficient than those made by girls. Another recent discovery is that the size, shape and efficiencies of the placenta can change over years of time with very narrow confidence limits. This suggests that the growth of the placenta within a population of women is strongly affected by their nutritional environment. Even though it is known that an individual placenta can expand to improve its nutrient acquisition capacity in the first 2/3rd of gestation, the mechanisms by which placentas grow in response to a specific nutritional environment are not known. Discovering those mechanisms is the task of the current generation of scientists. While it may seem obvious that good nutrition is highly important for women who are pregnant because it supports optimal placentation and fetal development, more research is needed to determine the mechanisms by which maternal nutrition, placenta growth and fetal health are related.
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Uteroplacental insufficiency causes intrauterine growth retardation (IUGR) and subsequent low birth weight, which predisposes the affected newborn towards adult Syndrome X. Individuals with Syndrome X suffer increased morbidity from adult ischemic heart disease. Myocardial ischemia initiates a defensive increase in cardiac glucose metabolism, and individuals with Syndrome X demonstrate reduced insulin sensitivity and reduced glucose uptake. Glucose transporters GLUT1 and GLUT4 facilitate glucose uptake across cardiac plasma membranes, and hexokinase II (HKII) is the predominant hexokinase isoform in adult cardiac tissue. We therefore hypothesized that GLUT1, GLUT4 and HKII gene expression would be reduced in heart muscle of growth-retarded rats, and that reduced gene expression would result in reduced myocardial glucose uptake. To prove this hypothesis, we measured cardiac GLUT1 and GLUT4 mRNA and protein in control IUGR rat hearts at day 21 and at day 120 of life. HKII mRNA quantification and 2-deoxyglucose-uptake studies were performed in day-120 control and IUGR cardiac muscle. Both GLUT1 and GLUT4 mRNA and protein were significantly reduced at day 21 and at day 120 of life in IUGR hearts. HKII mRNA was also reduced at day 120. Similarly, both basal and insulin-stimulated glucose uptake were significantly reduced in day-120 IUGR cardiac muscle. We conclude that adult rats showing IUGR as a result of uteroplacental insufficiency express significantly less cardiac GLUT1 and GLUT4 mRNA and protein than control animals (which underwent sham operations), and that this decrease in gene expression occurs in parallel with reduced myocardial glucose uptake. We speculate that this reduced GLUT gene expression and glucose uptake contribute towards mortality from ischemic heart disease seen in adults born with IUGR.
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Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (EC) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than controls. HGF concentrations were also lower in islet EC conditioned media (ECCM) from IUGR, and islets incubated with control islet ECCM responded by increasing insulin content, which was absent with IUGR ECCM. The effect of ECCM on islet insulin content was blocked with an inhibitory anti-HGF antibody. The HGF receptor was not different between control and IUGR islets, but VEGFA was lower and the high affinity VEGF receptor higher in IUGR islets and ECs, respectively. These findings show that paracrine actions from EC increase islet insulin content, and in IUGR EC secretion of HGF was diminished. Given the potential feed forward regulation of β-cell VEGFA and islet EC HGF, these two growth factors are highly integrated in normal pancreatic islet development and this regulation is decreased in IUGR fetuses resulting in lower pancreatic islet insulin concentrations and insulin secretion.
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Fatty acids are critical for normal fetal development, but may also influence placental function. We have previously reported that oleic acid (OA) stimulates amino acid transport in primary human trophoblast (PHTs) cells. In other tissues, saturated and unsaturated fatty acids have distinct effects on cellular signaling, for instance palmitic acid (PA) but not OA reduces IκBα expression. We hypothesized that saturated and unsaturated fatty acids differentially affect trophoblast amino acid transport and cellular signaling. To test this hypothesis, PHTs were cultured in docosahexaenoic acid (DHA; 50 µM), OA (100 µM), PA (100 µM). DHA and OA were also combined to test whether DHA could counteract OA stimulatory effect on amino acid transport. The effects of the fatty acids were compared against vehicle control. Amino acid transport was measured by isotope-labeled tracers. Activation of inflammatory related signaling pathways and mechanistic target of rapamycin (mTOR) pathway were determined by Western blot. Exposing PHTs cells to DHA for 24 hours reduced amino acid transport and phosphorylation of p38 MAPK, STAT3, mTOR, 4EBP1, and rpS6. In contrast, OA increased amino acid transport and phosphorylation of ERK, mTOR, S6K1, and rpS6. Combining DHA with OA increased amino acid transport and rpS6 phosphorylation. PA did not affect amino acid transport but reduced IĸBα expression. In conclusion, these fatty acids differentially regulate placental amino acid transport and cellular signaling. Together these findings suggest that dietary fatty acids could alter the intrauterine environment by modifying placental function, thereby having long-lasting effects on the developing fetus.
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BACKGROUND Implantation and early embryo development are finely regulated processes in which several molecules are involved. Evidence that thyroid hormones (TH: T4 and T3) might be part of this machinery is emerging. An increased demand for TH occurs during gestation, and any alteration in maternal thyroid physiology has significant implications for both maternal and fetal health. Not only overt but also subclinical hypothyroidism is associated with infertility as well as with obstetric complications, including disruptions and disorders of pregnancy, labor, delivery, and troubles in early neonatal life.
Developmental programming is a rapidly advancing discipline of great importance to basic scientists and health professionals alike. This text integrates, for the first time, contributions from world experts to explore the role of the placenta in developmental programming. The book considers the materno-fetal supply line, and how perturbations of placental development impact on its functional capacity. Chapters examine ways in which environmental, immunological and vascular insults regulate expression of conventional and imprinted genes, along with their impact on placental shape and size, transport, metabolism and endocrine function. Research in animal models is integrated with human clinical and epidemiological data, and questions for future research are identified. Transcripts of discussions between the authors allow readers to engage with controversial issues. Essential reading for researchers in placental biology and developmental programming, as well as specialists and trainees in the wider field of reproductive medicine.
In his Letter to the Editor, Carbillon (1) maintains that our mouse model of maternal obesity leading to fetal overgrowth (2) may not be relevant for the clinical condition because the fetal/placental weight ratio was not decreased, as is sometimes found in obese pregnant women. We disagree with Carbillon’s (1) assessment.
The discovery of a link between in utero experience and later metabolic and cardiovascular disease is one of the most important advances in epidemiology research of recent years. There is increasing evidence that alterations in the fetal environment may have long-term consequences on cardiovascular, metabolic, and endocrine pathophysiology in adult life. This process has been termed programming, and we have shown that undernutrition of the mother during gestation leads to programming of hyperphagia, obesity, hypertension, hyperinsulinemia, and hyperleptinemia in the offspring. Using this model of maternal undernutrition throughout pregnancy combined with postnatal hypercaloric nutrition of the offspring, we examined the effects of IGF-I therapy. Virgin Wistar rats (age 75 ± 5 d, n = 20 per group) were time mated and randomly assigned to receive food either ad libitum or 30% of ad libitum intake (UN) throughout pregnancy. At weaning, female offspring were assigned to one of two diets (control or hypercaloric[ 30% fat]). Systolic blood pressure was measured at day 175 and following infusion with 3 μg/g per day recombinant human IGF-1 (rh-IGF-I) by minipump for 14 d. Before treatment, UN offspring were hyperinsulinemic, hyperleptinemic, hyperphagic, obese, and hypertensive on both diets, compared with ad libitum offspring and this was exacerbated by hypercaloric nutrition. IGF-I treatment increased body weight in all treated animals. However, systolic blood pressure, food intake, retroperitoneal and gonadal fat pad weights, and plasma leptin and insulin concentrations were markedly reduced with IGF-I treatment. IGF-I treatment resulted in a 3- to 5-fold increase in 38–44 kDa and 28–30 kDa IGF binding proteins, although in UN animals, there was an impaired and differential up-regulation of these insulin-like growth factor binding proteins following IGF-I treatment. The 24-kDa IGF binding protein representing IGF binding protein-4 was down-regulated in all IGF-I-treated animals, but the decrease was more marked in UN animals. Our data suggest that IGF-I treatment alleviates hyperphagia, obesity, hyperinsulinemia, hyperleptinemia, and hypertension in rats programmed to develop the metabolic syndrome X.
Intrauterine programming of the somatotropic axis has been hypothesized in cases of intrauterine growth retardation. To study the effects of birth weight and body composition on GH sensitivity. Cross-sectional study with a single GH administration to assess GH sensitivity. Department of Pediatric Endocrinology of an academic medical center. One hundred normal short children from 4 to 17 years old (44 girls, 56 boys) separated into 4 groups: early childhood (4-8 years, n = 14), late childhood (9-12 years, pubertal stage 1, n = 30), early puberty (10-15 years, stage 2, n = 32), and mid-puberty (12-17 years, stages 3 and 4, n = 24). Intervention and main outcome measure: Serum IGF-1 at baseline and 24 hours after a single administration of GH (2 mg/m(2)). Delta IGF-1 significantly increased across the groups (p < 0.0001) with no gender difference, whereas the percentage of change in IGF-1 was similar (47 ± 32%). Independent predictors of delta IGF-1 were birth weight SD score, fat percentage, fasting insulin (all positive predictors) and free fatty acids (negative predictor), with age, puberty, and baseline IGF-1 as adjusting variables (multiple R = 0.73, p < 0.0001). Independent predictors of the percentage of change in IGF-1 were birth weight SD score, fat percentage, and baseline IGF-1 (multiple R = 0.43, p < 0.001). This study suggests that in cases of low birth weight, intrauterine programming of GH sensitivity may be an adaptation to an expected poor postnatal nutritional environment, serving to restrict the anabolic action of GH. Conversely, postnatal excess energy stores may promote the anabolic action of GH.