Owen R. Vaughan

Adaptations in placental phenotype support fetal growth during undernutrition of pregnant mice

Undernutrition during pregnancy reduces birth weight and programmes adult phenotype with consequences for life expectancy, but its effects on the phenotype of the placenta, responsible for supplying nutrients for fetal growth, remain largely unknown. Using molecular, morphological and functional analyses, placental phenotype was examined in mice during restriction of dietary intake to 80% of control from day 3 of pregnancy. At day 16, undernutrition reduced placental, but not fetal, weight in association with decreased junctional zone volume and placental expression of glucose transporter Slc2a1. At day 19, both placental and fetal weights were reduced in undernourished mice (91% and 87% of control, respectively, P < 0.01), as were the volume and surface area of the labyrinthine zone responsible for placental nutrient transfer (85% and 86%, respectively, P < 0.03). However, unidirectional materno‐fetal clearance of tracer glucose was maintained and methyl‐aminoisobutyric acid increased 166% (P < 0.005) per gram of undernourished placenta, relative to controls. This was associated with an 18% and 27% increased placental expression of glucose and system A amino acid transporters Slc2a1 and Slc38a2, respectively, at day 19 (P < 0.04). At both ages, undernutrition decreased expression of the placental specific transcript of the Igf2 gene by 35% (P < 0.01), although methylation of its promoter was unaffected. The placenta, therefore, adapts to help maintain fetal growth when its own growth is compromised by maternal undernutrition. Consequently, placental phenotype is responsive to environmental conditions and may help predict the risk of adult disease programmed in utero.

An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory

In developed societies, high‐sugar and high‐fat (HSHF) diets are now the norm and are increasing the rates of maternal obesity during pregnancy. In pregnant rodents, these diets lead to cardiovascular and metabolic dysfunction in their adult offspring, but the intrauterine mechanisms involved remain unknown. This study shows that, relative to standard chow, HSHF feeding throughout mouse pregnancy increases maternal adiposity (+30%, P<0.05) and reduces fetoplacental growth at d 16 (–10%, P<0.001). At d 19, however, HSHF diet group pup weight had normalized, despite the HSHF diet group placenta remaining small and morphologically compromised. This altered fetal growth trajectory was associated with enhanced placental glucose and amino acid transfer (+35%, P<0.001) and expression of their transporters (+40%, P<0.024). HSHF feeding also up‐regulated placental expression of fatty acid transporter protein, metabolic signaling pathways (phosphoinositol 3‐kinase and mitogen‐activated protein kinase), and several growth regulatory imprinted genes (Igf2, Dlk1, Snrpn, Grb10, and H19) independently of changes in DNA methylation. Obesogenic diets during pregnancy, therefore, alter maternal nutrient partitioning, partly through changes in the placental phenotype, which helps to meet fetal nutrient demands for growth near term. However, by altering provision of specific nutrients, dietary‐induced placental adaptations have important roles in programming development with health implications for the offspring in later life.—Sferruzzi‐Perri, A N., Vaughan, O. R., Haro, M., Cooper, W. N., Musial, B., Charalambous, M., Pestana, D., Ayyar, S., Ferguson‐Smith, A C., Burton, G. J., Con‐stancia, M., Fowden, A. L., An obesogenic diet during mouse pregnancy modifies maternal nutrient partitioning and the fetal growth trajectory. FASEB J. 27, 3928–3937 (2013). www.fasebj.org

Placental-specific Igf2 deficiency alters developmental adaptations to undernutrition in mice.

The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.

Maternal corticosterone regulates nutrient allocation to fetal growth in mice

•  Stress during pregnancy leads to fetal growth restriction. •  Natural glucocorticoids, such as corticosterone, are elevated by maternal stress and, hence, may mediate the effects of stress on fetal growth. •  This study shows that increasing corticosterone levels in pregnant mice limits fetal growth by reducing the amino acid supply and density of blood vessels in the placenta. •  The findings suggest that excess corticosterone may act to defend maternal resources during times of stress by constraining the placental allocation of nutrients to the fetus. •  The results also provide a potential mechanism by which stresses during pregnancy can program intrauterine growth and development with consequences in later life.

Dietary composition programmes placental phenotype in mice

Non‐technical summary  Studies on mice using severe diets show alterations in placental function, and fetal and adult health. However, little is known about the effects of mild dietary variations on the placenta. We investigated placental growth and function in mice fed diets with similar energy, but small differences in protein and sugar content. We show that placental adaptations occur to help support fetal growth: reduced protein leads to increased glucose transport and transporter gene expression in late pregnancy; just prior to term, amino acid transport expression correlated with protein intake; the placental endocrine compartment was smaller with the least dietary protein and somewhat larger with slight reduction in protein. Placentas in mice fed the least protein were better adapted than those exposed to slight protein reduction. These results may provide a good index of conditions in the womb and have important implications for the pre‐birth programming of life expectancy.

Environmental regulation of placental phenotype: implications for fetal growth

Environmental conditions during pregnancy determine birthweight, neonatal viability and adult phenotype in human and other animals. In part, these effects may be mediated by the placenta, the principal source of nutrients for fetal development. However, little is known about the environmental regulation of placental phenotype. Generally, placental weight is reduced during suboptimal conditions like maternal malnutrition or hypoxaemia but compensatory adaptations can occur in placental nutrient transport capacity to help maintain fetal growth. In vivo studies show that transplacental glucose and amino acid transfer adapt to the prevailing conditions induced by manipulating maternal calorie intake, dietary composition and hormone exposure. These adaptations are due to changes in placental morphology, metabolism and/or abundance of specific nutrient transporters. This review examines environmental programming of placental phenotype with particular emphasis on placental nutrient transport capacity and its implications for fetal growth, mainly in rodents. It also considers the systemic, cellular and molecular mechanisms involved in signalling environmental cues to the placenta. Ultimately, the ability of the placenta to balance the competing interests of mother and fetus in resource allocation may determine not only the success of pregnancy in producing viable neonates but also the long-term health of the offspring.

Hormonal and nutritional drivers of intrauterine growth.

Purpose of review Size at birth is critical in determining life expectancy with both small and large neonates at risk of shortened life spans. This review examines the hormonal and nutritional drivers of intrauterine growth with emphasis on the role of foetal hormones as nutritional signals in utero. Recent findings Nutrients drive intrauterine growth by providing substrate for tissue accretion, whereas hormones regulate nutrient distribution between foetal oxidative metabolism and mass accumulation. The main hormonal drivers of intrauterine growth are insulin, insulin-like growth factors and thyroid hormones. Together with leptin and cortisol, these hormones control cellular nutrient uptake and the balance between accretion and differentiation in regulating tissue growth. They also act indirectly via the placenta to alter the materno-foetal supply of nutrients and oxygen. By responding to nutrient and oxygen availability, foetal hormones optimize the survival and growth of the foetus with respect to its genetic potential, particularly during adverse conditions. However, changes in the intrauterine growth of individual tissues may alter their function permanently. Summary In both normal and compromised pregnancies, intrauterine growth is determined by multiple hormonal and nutritional drivers which interact to produce a specific pattern of intrauterine development with potential lifelong consequences for health.

Corticosterone alters materno-fetal glucose partitioning and insulin signalling in pregnant mice.

Glucocorticoids regulate fetal and adult glucose metabolism, in part by influencing the actions of insulin. However, their effects on materno‐fetal glucose partitioning remain largely unknown. In the present study, when pregnant mice were given the natural glucocorticoid, corticosterone, plasma insulin concentrations and liver insulin‐signalling increased but the blood glucose concentration remained normal. However, in the placenta, glucose transport was reduced in association with the lower activity of some insulin signalling proteins, depending on the day of pregnancy and maternal food intake. In both liver and placenta, there was increased expression of the Redd1 (Ddit4) gene when the plasma corticosterone concentration was raised. The results show that maternal glucocorticoids interact with signalling pathways in the placenta to limit materno‐fetal glucose partitioning.

Review: Endocrine regulation of placental phenotype

Hormones have an important role in regulating fetal development. They act as environmental signals and integrate tissue growth and differentiation with relation to nutrient availability. While hormones control the developmental fate of resources available to the fetus, the actual supply of nutrients and oxygen to the fetus depends on the placenta. However, much less is known about the role of hormones in regulating placental development, even though the placenta has a wide range of hormone receptors and produces hormones itself from early in gestation. The placenta is, therefore, exposed to hormones by autocrine, paracrine and endocrine mechanisms throughout its lifespan. It is known to adapt its phenotype in response to environmental cues and fetal demand signals, particularly when there is a disparity between the fetal genetic drive for growth and the nutrient supply. These adaptive responses help to maintain fetal growth during adverse conditions and are likely to depend, at least in part, on the hormonal milieu. This review examines the endocrine regulation of placental phenotype with particular emphasis on the glucocorticoid hormones. It focuses on the availability of placental hormone receptors and on the effects of hormones on the morphology, transport capacity and endocrine function of the placenta.

Placental phenotype and resource allocation to fetal growth are modified by the timing and degree of hypoxia during mouse pregnancy

Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth. In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia. Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age. Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia. There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies.