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CURATOR
A pinboard by
Hannah Yong

Discovering how your first nine months shapes the rest of your life...

PINBOARD SUMMARY

What is the role of placental signalling in determining lifelong offspring metabolic health?

Birthweight predicts an individual’s future health and life expectancy. Globally, fetal growth is compromised in approximately 1 in 4 pregnancies. Such babies are at high risk of poor future health, developing diseases such as diabetes and obesity in later life, which may lead to premature death. Despite this, the regulation of fetal growth remains poorly understood. Fetal growth depends on the placenta, an organ that develops to transfer nutrients from mother to fetus. However, the placenta also secretes signalling factors that may adapt the mother’s metabolism to support fetal nutrient supply during pregnancy. Nevertheless, the precise role of placental signalling function in fetal growth and programming future health is unknown. My lab has generated unique mouse models where the signalling function of the placenta is specifically disrupted, leaving placental transport function, mother and fetus unmanipulated. We aim to examine the effect of altered placental signalling function on fetal growth, birth outcomes and metabolic health of offspring in later life. We will also identify the mechanisms involved in transmitting the memories of an adverse in utero environment due to malfunction of placental signalling. These findings will ultimately enhance our understanding of the causes of abnormal fetal growth, and aid the development of new tools to diagnose and therapies to improve outcomes of compromised pregnancies.

14 ITEMS PINNED

Placental Origins of Chronic Disease.

Abstract: Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.

Pub.: 09 Sep '16, Pinned: 29 Jun '17

Biological features of placental programming

Abstract: 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.

Pub.: 20 Oct '16, Pinned: 29 Jun '17

Birth weight-for-gestational age is associated with DNA methylation at birth and in childhood

Abstract: Background Both higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. Methods/results Participants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7–10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., β (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described. Conclusions We identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood. Background Both higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. BackgroundBoth higher and lower fetal growth are associated with cardio-metabolic health later in life, suggesting that prenatal developmental programming determines long-term cardiovascular disease risk. Epigenetic mechanisms, which orchestrate fetal growth and development, may offer insight on the early programming of health and disease. We investigated whether birth weight-for-gestational is associated with DNA methylation at birth and mid-childhood, measured via the Infinium 450K array. Methods/results Participants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7–10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., β (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described. Methods/resultsParticipants were from Project Viva, a pre-birth cohort of pregnant women and their children in Eastern Massachusetts. After exclusion of participants with maternal type 1 or 2 diabetes and gestational age <34 weeks, we used DNA methylation assays from 476 venous umbilical cord blood samples and a subset of 235 who additionally had peripheral blood samples available in mid-childhood (age 7–10 years). Among 392,918 CpG sites analyzed, birth weight-for-gestational age z-score was associated with cord blood DNA methylation at 34 CpGs (false discovery rate P < 0.05), after adjusting for maternal age, race/ethnicity, education, smoking, parity, delivery mode, pre-pregnancy BMI, gestational diabetes status, child sex, and estimated cord blood cell proportions based on a cord blood reference panel. Two of these CpGs were previously reported in epigenome-wide analyses of birth weight, and several other CpGs map to genes relevant to fetal growth and development. Namely, higher birth weight-for-gestational age was associated with higher methylation at four CpGs at the PBX1 locus (e.g., β (95% CI) for lead signal at cg06750897 = 1.9 (1.2, 2.6)), which encodes a transcription factor that regulates embryonic development. Birth weight-for-gestational age was also associated with mid-childhood blood DNA methylation at four of the 34 CpGs identified in cord blood analyses, including sites at the PBX1 locus described.zPPBX1PBX1 Conclusions We identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood. ConclusionsWe identified CpG sites where birth weight-for-gestational age was associated with DNA methylation at birth, and for a subset of these sites, birth weight-for-gestational age was also associated with DNA methylation at mid-childhood.

Pub.: 16 Nov '16, Pinned: 29 Jun '17

Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth.

Abstract: The placenta is the main determinant of fetal growth and development in utero. It supplies all the nutrients and oxygen required for fetal growth and secretes hormones that facilitate maternal allocation of nutrients to the fetus. Furthermore, the placenta responds to nutritional and metabolic signals in the mother by altering its structural and functional phenotype which can lead to changes in maternal resource allocation to the fetus. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This review discusses the role of the insulin-like growth factors (IGFs) in controlling placental resource allocation to fetal growth, particularly in response to adverse gestational environments. In particular, it assesses the impact of the IGFs and their signalling machinery on placental morphogenesis, substrate transport and hormone secretion, primarily in the laboratory species, although it draws on data from human and other species where relevant. It also considers the role of the IGFs as environmental signals in linking resource availability, to fetal growth through changes in the morphological and functional phenotype of the placenta. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing adult-onset diseases in later life, understanding the role of IGFs during pregnancy in regulating placental resource allocation to fetal growth is important for identifying the mechanisms underlying the developmental programming of offspring phenotype by suboptimal intrauterine growth. This article is protected by copyright. All rights reserved.

Pub.: 25 Mar '17, Pinned: 29 Jun '17

Leptin and its Receptors in Human Placenta of Small, Adequate, and Large for Gestational Age Newborns.

Abstract: Alterations in birth weight impact postnatal outcome and adult metabolic health. Therefore, fetal growth regulation is crucial for preventing chronic metabolic diseases. Leptin has been suggested to play an important role in placental and fetal growth, albeit its specific mechanisms of action have not been elucidated. The aim of this study was to analyze leptin concentrations in placenta, cord blood, and maternal blood of SGA, AGA, and LGA (small, adequate and large for gestational age, respectively) newborns, as well as placental leptin receptor (LEPRa and LEPRb) protein expression. We performed a cross-sectional comparative study in 3 groups of healthy mothers and their term newborns at delivery (SGA, AGA, and LGA, n=20 per group). Placental, maternal blood, and cord blood leptin content were measured by ELISA. Placental LEPRa and LEPRb protein expression were determined by Western Blot. Maternal leptin concentrations correlated positively with maternal weight before and at the end of gestation, without differences between groups. Cord leptin is higher in LGA and lower in SGA, whereas placental leptin is higher in SGA. Placental leptin was inversely correlated with placental weight, independently from maternal weight and gestational age. Both LEPRa and LEPRb expression are lower in SGA, while LEPRa positively correlated with placental weight and birthweight. The current findings indicate that placental leptin and its receptors are differentially expressed in SGA, AGA, and LGA newborns. We suggest that placental leptin and LEPR protein expression may influence placental growth and thus, birth weight.

Pub.: 30 Mar '17, Pinned: 29 Jun '17

Sex-specific differences and developmental programming for diseases in later life.

Abstract: Epidemiological data indicate that developmental programming of various non-communicable diseases (NCDs) occurs as a consequence of altered maternal metabolic and physiological status due to a number of environmental insults during pregnancy. Sex-specific differences have also been reported in most NCDs. Evidence suggests that beginning from conception, the maternal and neonatal metabolic environment, including hormones, contributes to sex-specific placental development. The placenta then regulates the sex-specific differences in NCDs via the epigenetic mechanisms that are further affected by hormones. Male and female embryos have been reported to exhibit sex-specific transcriptional regulation, and it is suggested that their development can be considered as separate processes beginning from conception. This review summarises various animal and human studies examining sex-specific differences in NCDs due to differential placental epigenetic developmental programming. An overview of possible mechanisms underlying this is also discussed. Further, the review describes sex-specific changes in the structure and function of the placenta in pregnancies complicated by fetal growth restriction, pre-eclampsia and preterm birth. Thus, because sex-specific differences are associated with fetal outcome and survival, future studies need to take into consideration the sex of the fetus while explaining the concept of the developmental origins of health and disease.

Pub.: 06 Apr '17, Pinned: 29 Jun '17

Impact of Metabolic Hormones Secreted in Human Breast Milk on Nutritional Programming in Childhood Obesity.

Abstract: Obesity is the most common metabolic disease whose prevalence is increasing worldwide. This condition is considered a serious public health problem due to associated comorbidities such as diabetes mellitus and hypertension. Perinatal morbidity related to obesity does not end with birth; this continues affecting the mother/infant binomial and could negatively impact on metabolism during early infant nutrition. Nutrition in early stages of growth may be essential in the development of obesity in adulthood, supporting the concept of "nutritional programming". For this reason, breastfeeding may play an important role in this programming. Breast milk is the most recommended feeding for the newborn due to the provided benefits such as protection against obesity and diabetes. Health benefits are based on milk components such as bioactive molecules, specifically hormones involved in the regulation of food intake. Identification of these molecules has increased in recent years but its action has not been fully clarified. Hormones such as leptin, insulin, ghrelin, adiponectin, resistin, obestatin and insulin-like growth factor-1 copeptin, apelin, and nesfatin, among others, have been identified in the milk of normal-weight women and may influence the energy balance because they can activate orexigenic or anorexigenic pathways depending on energy requirements and body stores. It is important to emphasize that, although the number of biomolecules identified in milk involved in regulating food intake has increased considerably, there is a lack of studies aimed at elucidating the effect these hormones may have on metabolism and development of the newborn. Therefore, we present a state-of-the-art review regarding bioactive compounds such as hormones secreted in breast milk and their possible impact on nutritional programming in the infant, analyzing their functions in appetite regulation.

Pub.: 28 Jun '17, Pinned: 29 Jun '17

The Wuhan Twin Birth Cohort (WTBC).

Abstract: The Wuhan Pre/Post-Natal Twin Birth Registry (WPTBR) is one of the largest twin birth registries with comprehensive medical information in China. It recruits women from the first trimester of pregnancy and their twins from birth. From January 2006 to May 2016, the total number of twins enrolled in WPTBR is 13,869 twin pairs (27,553 individuals). The WPTBR initiated the Wuhan Twin Birth Cohort (WTBC). The WTBC is a prospective cohort study carried out through incorporation of three samples. The first one comprises 6,920 twin pairs, and the second one, 6,949 twin pairs. Both are population-based samples linked to the WPTBR and include pre- and post-natal information from WPTBR. The second sample includes neonatal blood spots as well. Using a hospital-based approach, we recently developed a third sample with a target enrolment of 1,000 twin pairs and their mothers. These twins are invited, via their parents, to participate in a periodic health examination from the first trimester of pregnancy to 18 years. Biological samples are collected initially from the mother, including blood, urine, cord blood, cord, amniotic fluid, placenta, breast milk and meconium, and vaginal secretions, and later from the twins, including meconium, stool, urine, and blood. This article describes the design, recruitment, follow-up, data collection, and measures, as well as ongoing and planned analyses at the WTBC. The WTBC offers a unique opportunity to follow women from prenatal to postnatal, as well as follow-up of their twins. This cohort study will expand the understanding of genetic and environmental influences on pregnancy and twins' development in China.

Pub.: 28 Jun '17, Pinned: 29 Jun '17

Maternal plasma phosphatidylcholine polyunsaturated fatty acids during pregnancy and offspring growth and adiposity.

Abstract: Polyunsaturated fatty acids (PUFA) are essential for offspring development, but it is less clear whether pregnancy PUFA status affects growth and adiposity.In 985 mother-offspring pairs from the ongoing Singaporean GUSTO cohort, we analyzed the associations between offspring growth and adiposity outcomes until age 5 years and five PUFAs of interest, measured in maternal plasma at 26-28 weeks' gestation: linoleic acid (LA), arachidonic acid, α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). We measured fetal growth by ultrasound (n=924), neonatal body composition (air displacement plethysmography (n=252 at birth, and n=317 at age 10 days), and abdominal magnetic resonance imaging (n=317)), postnatal growth (n=979) and skinfold thicknesses (n=981). Results were presented as regression coefficients for a 5% increase in PUFA levels.LA levels were positively associated with birthweight (β (95% CI): 0.04 (0.01, 0.08) kg), body mass index (0.13 (0.02, 0.25) kg/m(2)), head circumference (0.11 (0.03, 0.19) cm), and neonatal abdominal adipose tissue volume (4.6 (1.3, 7.8) mL for superficial subcutanous tissue, and 1.2 (0.1, 2.4) mL for internal tissue), but not with later outcomes. DHA levels, although not associated with birth outcomes, were related to higher postnatal length/height: 0.63 (0.09, 1.16) cm at 12 months and 1.29 (0.34, 2.24) cm at 5 years.LA was positively associated with neonatal body size, and DHA with child height. Maternal PUFA status during pregnancy may influence fetal and child growth and adiposity.

Pub.: 28 Jun '17, Pinned: 29 Jun '17

Maternal plasma n-3 and n-6 polyunsaturated fatty acids during pregnancy and features of fetal health: Fetal growth velocity, birth weight and duration of pregnancy.

Abstract: Maternal fatty acids are essential for fetal growth and development. Here, we examine associations between maternal mid-pregnancy plasma n-3 and n-6 polyunsaturated fatty acids (PUFAs) and fetal health determined by fetal growth velocity, birth weight and duration of pregnancy.Participants were 6974 pregnant women and their infants from a population-based birth cohort, the Generation R Study. Maternal plasma n-3:n-6 PUFA ratio and n-3 and n-6 PUFA percentage in glycerophospholipids in mid-pregnancy were related to fetal growth velocity calculated from repeatedly measured weight, length and head circumference, birth weight, and duration of pregnancy.A higher maternal mid-pregnancy n-3:n-6 PUFA ratio was associated with a higher growth velocity of the fetal weight (β = 0.082 SD-score/week, 95% CI 0.055; 0.108, P < 0.001), length (β = 0.085 SD-score/week, 95% CI 0.052; 0.119, P < 0.001); and head (β = 0.055 SD-score/week, 95% CI 0.019; 0.091, P = 0.003). We also observed positive associations between n-3:n-6 PUFA ratio and birth weight (β = 0.76 SD-score, 95% CI 0.22; 1.29, P = 0.006), and duration of pregnancy (β = 1.32 weeks, 95% CI 0.24; 2.40, P = 0.02).These results are consistent with the hypothesis that a higher n-3:n-6 PUFA ratio is important for fetal health.

Pub.: 28 Jun '17, Pinned: 29 Jun '17