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1.  Gestational Age and Neonatal Brain Microstructure in Term Born Infants: A Birth Cohort Study 
PLoS ONE  2014;9(12):e115229.
Objective
Understanding healthy brain development in utero is crucial in order to detect abnormal developmental trajectories due to developmental disorders. However, in most studies neuroimaging was done after a significant postnatal period, and in those studies that performed neuroimaging on fetuses, the quality of data has been affected due to complications of scanning during pregnancy. To understand healthy brain development between 37–41 weeks of gestational age, our study assessed the in utero growth of the brain in healthy term born babies with DTI scanning soon after birth.
Methods
A cohort of 93 infants recruited from maternity hospitals in Singapore underwent diffusion tensor imaging between 5 to 17 days after birth. We did a cross-sectional examination of white matter microstructure of the brain among healthy term infants as a function of gestational age via voxel-based analysis on fractional anisotropy.
Results
Greater gestational age at birth in term infants was associated with larger fractional anisotropy values in early developing brain regions, when corrected for age at scan. Specifically, it was associated with a cluster located at the corpus callosum (corrected p<0.001), as well as another cluster spanning areas of the anterior corona radiata, anterior limb of internal capsule, and external capsule (corrected p<0.001).
Conclusions
Our findings show variation in brain maturation associated with gestational age amongst ‘term’ infants, with increased brain maturation when born with a relatively higher gestational age in comparison to those infants born with a relatively younger gestational age. Future studies should explore if these differences in brain maturation between 37 and 41 weeks of gestational age will persist over time due to development outside the womb.
doi:10.1371/journal.pone.0115229
PMCID: PMC4275243  PMID: 25535959
2.  The association between maternal blood pressures and offspring size at birth in Southeast Asian women 
Background
Maternal blood pressures in pregnancy is an important determinant of offspring size at birth. However, the relationship between maternal blood pressures and offspring’s size at birth is not consistent and may vary between ethnic groups. We examined the relationship between maternal peripheral and central blood pressures and offspring size at birth in an Asian multi-ethnic cohort, and effect modifications by maternal ethnicity and obesity.
Methods
We used data from 713 participants in the Growing Up in Singapore Towards Healthy Outcomes study consisting of pregnant Chinese, Malay and Indian women recruited from two tertiary hospitals between 2009 to 2010. Peripheral systolic and diastolic blood pressures (SBP and DBP), and central SBP and pulse pressure (PP) were measured around 27 weeks of gestation. Biometric parameters at birth were collected from medical records.
Results
After adjusting for maternal and fetal covariates, each 1-SD increase (10.0 mmHg) in central SBP was inversely associated with birth weight (−40.52 g; 95% confidence interval (CI) -70.66 to −10.37), birth length (−0.19 cm; −0.36 to −0.03), head circumference (−0.12 cm; −0.23 to −0.02) and placental weight (−11.16 g; −20.85 to −1.47). A one-SD (11.1 mmHg) increase in peripheral SBP was also associated with lower birth weight (−35.56 g; −66.57 to −4.54). The inverse relations between other blood pressure measures and offspring size at birth were observed but not statistically significant. Higher peripheral SBP and DBP and central SBP were associated with increased odds of low birth weight (defined as weight <2500 g) and small for gestational age (defined as <10th percentile for gestational age adjusted birth weight). Maternal adiposity modified these associations, with stronger inverse associations in normal weight women. No significant interactions were found with ethnicity.
Conclusions
Higher second-trimester peripheral and central systolic pressures were associated with smaller offspring size at birth, particularly in normal weight women. Findings from this study reinforces the clinical relevance of antenatal blood pressure monitoring.
Electronic supplementary material
The online version of this article (doi:10.1186/s12884-014-0403-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12884-014-0403-1
PMCID: PMC4259008  PMID: 25444649
Pregnancy; Blood pressures; Obesity; Birth weight
3.  Ethnic differences translate to inadequacy of high-risk screening for gestational diabetes mellitus in an Asian population: a cohort study 
Background
Universal and high-risk screening for gestational diabetes mellitus (GDM) has been widely studied and debated. Few studies have assessed GDM screening in Asian populations and even fewer have compared Asian ethnic groups in a single multi-ethnic population.
Methods
1136 pregnant women (56.7% Chinese, 25.5% Malay and 17.8% Indian) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort study were screened for GDM by 75-g oral glucose tolerance test (OGTT) at 26–28 weeks of gestation. GDM was defined using the World Health Organization (WHO) criteria. High-risk screening is based on the guidelines of the UK National Institute for Health and Clinical Excellence.
Results
Universal screening detected significantly more cases than high-risk screening [crude OR 2.2 (95% CI 1.7-2.8)], particularly for Chinese women [crude OR = 3.5 (95% CI 2.5-5.0)]. Pre-pregnancy BMI > 30 kg/m2 (adjusted OR = 3.4, 95% CI 1.5-7.9) and previous GDM history (adjusted OR = 6.6, 95% CI 1.2-37.3) were associated with increased risk of GDM in Malay women while GDM history was the only significant risk factor for GDM in Chinese women (adjusted OR = 4.7, 95% CI 2.0-11.0).
Conclusion
Risk factors used in high-risk screening do not sufficiently predict GDM risk and failed to detect half the GDM cases in Asian women. Asian women, particularly Chinese, should be screened to avoid under-diagnosis of GDM and thereby optimize maternal and fetal outcomes.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2393-14-345) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2393-14-345
PMCID: PMC4190487  PMID: 25273851
Universal screening; High risk screening; Gestational diabetes; Asians; Ethnic
4.  Childhood bone mineral content is associated with methylation status of the RXRA promoter at birth 
Maternal vitamin D deficiency has been associated with reduced offspring bone mineral accrual. Retinoid-X Receptor-alpha (RXRA) is an essential cofactor in the action of 1,25(OH)2-vitamin D, and RXRA methylation in umbilical cord DNA has been associated with later offspring adiposity. We tested the hypothesis that RXRA methylation in umbilical cord DNA collected at birth is associated with offspring skeletal development, assessed by dual-energy X-ray absorptiometry, in a population-based mother-offspring cohort (Southampton Women’s Survey). Relationships between maternal plasma 25(OH)-vitamin D concentrations and cord RXRA methylation were also investigated. In 230 children aged 4 years, higher % methylation at 4 out of 6 RXRA CpG sites measured was correlated with lower offspring % bone mineral content (%BMC) (β=−0.02 to −0.04%/SD, p=0.002 to 0.043) and BMC corrected for body size (β=−2.1 to −3.4g/SD, p=0.002 to 0.047), with a further site associated with %BMC only. Similar relationships for %BMC were observed in a second independent cohort (n=64). Maternal free 25(OH)-vitamin D index was negatively associated with methylation at one of these RXRA CpG sites (β=−3.3 SD/unit, p=0.03). In addition to the mechanistic insights afforded by associations between maternal free 25(OH)-vitamin D index, RXRA methylation in umbilical cord DNA, and childhood BMC, such epigenetic marks in early life might represent novel biomarkers for adverse bone outcomes in the offspring.
doi:10.1002/jbmr.2056
PMCID: PMC3836689  PMID: 23907847
Epigenetic; methylation; umbilical cord; RXRA; vitamin D; DXA
5.  Structural Connectivity Asymmetry in the Neonatal Brain 
NeuroImage  2013;75:187-194.
Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-world characteristics were exhibited, but did not differ between the two hemispheres, suggesting that neighboring brain regions connect tightly with each other, and that one region is only a few paths away from any other region within each hemisphere. Moreover, the neonatal brain showed greater structural efficiency in the left hemisphere than that in the right. In neonates, brain regions involved in motor, language, and memory functions play crucial roles in efficient communication in the left hemisphere, while brain regions involved in emotional processes play crucial roles in efficient communication in the right hemisphere. These findings suggest that even at birth, the topology of each cerebral hemisphere is organized in an efficient and compact manner that maps onto asymmetric functional specializations seen in adults, implying lateralized brain functions in infancy.
doi:10.1016/j.neuroimage.2013.02.052
PMCID: PMC3959921  PMID: 23501049
cerebral asymmetry; structural connectivity network; diffusion tensor imaging; neonates; tractography
7.  PPTOX III: Environmental Stressors in the Developmental Origins of Disease—Evidence and Mechanisms 
Toxicological Sciences  2012;131(2):343-350.
Fetal and early postnatal development constitutes the most vulnerable time period of human life in regard to adverse effects of environmental hazards. Subtle effects during development can lead to functional deficits and increased disease risk later in life. The hypothesis stating that environmental exposures leads to altered programming and, thereby, to increased susceptibility to disease or dysfunction later in life has garnered much support from both experimental and epidemiological studies. Similar observations have been made on the long-term impact of nutritional unbalance during early development. In an effort to bridge the fields of nutritional and environmental developmental toxicity, the Society of Toxicology sponsored this work. This report summarizes novel findings in developmental toxicity as reported by select invited experts and meeting attendees. Recommendations for the application and improvement of current and future research efforts are also presented.
doi:10.1093/toxsci/kfs267
PMCID: PMC3551422  PMID: 22956631
developmental origins of health and disease; developmental toxicity; early-life exposure.
8.  Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming 
BMC Genomics  2014;15:49.
Background
Maternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.
Results
We show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring.
Conclusions
We propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.
doi:10.1186/1471-2164-15-49
PMCID: PMC3899603  PMID: 24447410
Leptin; Fetal programming; Development; Obesity; Thrifty phenotype; Antigen presentation; Inflammation
9.  Tissue-Specific 5′ Heterogeneity of PPARα Transcripts and Their Differential Regulation by Leptin 
PLoS ONE  2013;8(6):e67483.
The genes encoding nuclear receptors comprise multiple 5′untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3–13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors.
doi:10.1371/journal.pone.0067483
PMCID: PMC3692471  PMID: 23825665
10.  How evolutionary principles improve the understanding of human health and disease 
Evolutionary Applications  2011;4(2):249-263.
An appreciation of the fundamental principles of evolutionary biology provides new insights into major diseases and enables an integrated understanding of human biology and medicine. However, there is a lack of awareness of their importance amongst physicians, medical researchers, and educators, all of whom tend to focus on the mechanistic (proximate) basis for disease, excluding consideration of evolutionary (ultimate) reasons. The key principles of evolutionary medicine are that selection acts on fitness, not health or longevity; that our evolutionary history does not cause disease, but rather impacts on our risk of disease in particular environments; and that we are now living in novel environments compared to those in which we evolved. We consider these evolutionary principles in conjunction with population genetics and describe several pathways by which evolutionary processes can affect disease risk. These perspectives provide a more cohesive framework for gaining insights into the determinants of health and disease. Coupled with complementary insights offered by advances in genomic, epigenetic, and developmental biology research, evolutionary perspectives offer an important addition to understanding disease. Further, there are a number of aspects of evolutionary medicine that can add considerably to studies in other domains of contemporary evolutionary studies.
doi:10.1111/j.1752-4571.2010.00164.x
PMCID: PMC3352556
contemporary evolution; developmental plasticity; epigenetics; evolutionary medicine; life history; mismatch; selection; trade-off
11.  Evolving a definition of disease 
Archives of Disease in Childhood  2007;92(12):1053-1054.
Perspective on the paper by Reinehr et al (see page 1067)
doi:10.1136/adc.2007.126318
PMCID: PMC2066098  PMID: 18032637
12.  Early life opportunities for prevention of diabetes in low and middle income countries 
BMC Public Health  2012;12:1025.
Background
The global burden of diabetes and other non-communicable diseases is rising dramatically worldwide and is causing a double poor health burden in low- and middle-income countries. Early life influences play an important part in this scenario because maternal lifestyle and conditions such as gestational diabetes and obesity affect the risk of diabetes in the next generation. This indicates important periods during the lifecourse when interventions could have powerful affects in reducing incidence of non-communicable diseases. However, interventions to promote diet and lifestyle in prospective parents before conception have not received sufficient attention, especially in low- and middle-income countries undergoing socio-economic transition.
Discussion
Interventions to produce weight loss in adults or to reduce weight gain in pregnancy have had limited success and might be too late to produce the largest effects on the health of the child and his/her later risk of non-communicable diseases. A very important factor in the prevention of the developmental component of diabetes risk is the physiological state in which the parents enter pregnancy. We argue that the most promising strategy to improve prospective parents’ body composition and lifestyle is the promotion of health literacy in adolescents. Multiple but integrated forms of community-based interventions that focus on nutrition, physical activity, family planning, breastfeeding and infant feeding practices are needed. They need to address the wider social economic context in which adolescents live and to be linked with existing public health programmes in sexual and reproductive health and maternal and child health initiatives.
Summary
Interventions aimed at ensuring a healthy body composition, diet and lifestyle before pregnancy offer a most effective solution in many settings, especially in low- and middle-income countries undergoing socio-economic transition. Preparing a mother, her partner and her future child for “the 1000 days”, whether from planned or unplanned conception would break the cycle of risk and demonstrate benefit in the shortest possible time. Such interventions will be particularly important in adolescents and young women in disadvantaged groups and can improve the physiological status of the fetus as well as reduce the prevalence of pregnancy conditions such as gestational diabetes mellitus which both predispose to non-communicables diseases in both the mother and her child. Pre-conception interventions require equipping prospective parents with the necessary knowledge and skills to make healthy lifestyle choices for themselves and their children. Addressing the promotion of such health literacy in parents-to-be in low- and middle-income countries requires a wider social perspective. It requires a range of multisectoral agencies to work together and could be linked to the issues of women’s empowerment, to reproductive health, to communicable disease prevention and to the Millennium Development Goals 4 and 5.
doi:10.1186/1471-2458-12-1025
PMCID: PMC3526388  PMID: 23176627
Adolescents; Diabetes; Health literacy; Interventions; Life-course; Non-communicable diseases; Gestational diabetes mellitus; Obesity
13.  Population Differences in Brain Morphology and Microstructure among Chinese, Malay, and Indian Neonates 
PLoS ONE  2012;7(10):e47816.
We studied a sample of 75 Chinese, 73 Malay, and 29 Indian healthy neonates taking part in a cohort study to examine potential differences in neonatal brain morphology and white matter microstructure as a function of ethnicity using both structural T2-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). We first examined the differences in global size and morphology of the brain among the three groups. We then constructed the T2-weighted MRI and DTI atlases and employed voxel-based analysis to investigate ethnic differences in morphological shape of the brain from the T2-weighted MRI, and white matter microstructure measured by fractional anisotropy derived from DTI. Compared with Malay neonates, the brains of Indian neonates’ tended to be more elongated in anterior and posterior axis relative to the superior-inferior axis of the brain even though the total brain volume was similar among the three groups. Although most anatomical regions of the brain were similar among Chinese, Malay, and Indian neonates, there were anatomical variations in the spinal-cerebellar and cortical-striatal-thalamic neural circuits among the three populations. The population-related brain regions highlighted in our study are key anatomical substrates associated with sensorimotor functions.
doi:10.1371/journal.pone.0047816
PMCID: PMC3480429  PMID: 23112850
14.  Measuring the methylome in clinical samples 
Epigenetics  2012;7(10):1173-1187.
The Infinium Human Methylation450 BeadChip ArrayTM (Infinium 450K) is an important tool for studying epigenetic patterns associated with disease. This array offers a high-throughput, low cost alternative to more comprehensive sequencing-based methodologies. Here we compare data generated by interrogation of the same seven clinical samples by Infinium 450K and reduced representation bisulfite sequencing (RRBS). This is the largest data set comparing Infinium 450K array to the comprehensive RRBS methodology reported so far. We show good agreement between the two methodologies. A read depth of four or more reads in the RRBS data was sufficient to achieve good agreement with Infinium 450K. However, we observe that intermediate methylation values (20–80%) are more variable between technologies than values at the extremes of the bimodal methylation distribution. We describe careful processing of Infinium 450K data to correct for known limitations and batch effects. Using methodologies proposed by others and newly implemented and combined in this report, agreement of Infinium 450K data with independent techniques can be vastly improved.
doi:10.4161/epi.22102
PMCID: PMC3469459  PMID: 22964528
DNA methylation; InfiniumHD array; RRBS; genome-wide; clinical sample; EWAS
15.  Transcriptome Changes Affecting Hedgehog and Cytokine Signalling in the Umbilical Cord: Implications for Disease Risk 
PLoS ONE  2012;7(7):e39744.
Background
Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA.
Methods
The gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698–4151 g) and gestational ages (35–41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity.
Results
We found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome.
Conclusions
We studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk.
doi:10.1371/journal.pone.0039744
PMCID: PMC3393728  PMID: 22808055
16.  Developmental origins of non-communicable disease: Implications for research and public health 
Environmental Health  2012;11:42.
This White Paper highlights the developmental period as a plastic phase, which allows the organism to adapt to changes in the environment to maintain or improve reproductive capability in part through sustained health. Plasticity is more prominent prenatally and during early postnatal life, i.e., during the time of cell differentiation and specific tissue formation. These developmental periods are highly sensitive to environmental factors, such as nutrients, environmental chemicals, drugs, infections and other stressors. Nutrient and toxicant effects share many of the same characteristics and reflect two sides of the same coin. In both cases, alterations in physiological functions can be induced and may lead to the development of non-communicable conditions. Many of the major diseases – and dysfunctions – that have increased substantially in prevalence over the last 40 years seem to be related in part to developmental factors associated with either nutritional imbalance or exposures to environmental chemicals. The Developmental Origins of Health and Disease (DOHaD) concept provides significant insight into new strategies for research and disease prevention and is sufficiently robust and repeatable across species, including humans, to require a policy and public health response. This White Paper therefore concludes that, as early development (in utero and during the first years of postnatal life) is particularly sensitive to developmental disruption by nutritional factors or environmental chemical exposures, with potentially adverse consequences for health later in life, both research and disease prevention strategies should focus more on these vulnerable life stages.
doi:10.1186/1476-069X-11-42
PMCID: PMC3384466  PMID: 22715989
Environmental exposure; Fetal development; Non-communicable disease; Nutritional requirements; Prenatal exposure delayed effects
17.  Epigenetic Gene Promoter Methylation at Birth Is Associated With Child’s Later Adiposity 
Diabetes  2011;60(5):1528-1534.
OBJECTIVE
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
RESEARCH DESIGN AND METHODS
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5–95% range ≥10%, we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
RESULTS
In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4–31], P = 0.009, n = 64, and β = 20% [9–32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1–19], P = 0.023, n = 64 and β =12% [4–20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2–10] and β = 4% [1–7], respectively, both P = 0.002, n = 239).
CONCLUSIONS
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
18.  Prenatal Factors Contribute to the Emergence of Kwashiorkor or Marasmus in Severe Undernutrition: Evidence for the Predictive Adaptation Model 
PLoS ONE  2012;7(4):e35907.
Background
Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity.
Methodology/Principal Findings
We reviewed the records of all children admitted with severe acute malnutrition to the Tropical Metabolism Research Unit Ward of the University Hospital of the West Indies, Kingston, Jamaica during 1962–1992. We used Wellcome criteria to establish the diagnoses of kwashiorkor (n = 391), marasmus (n = 383), and marasmic-kwashiorkor (n = 375). We recorded participants' birth weights, as determined from maternal recall at the time of admission. Those who developed kwashiorkor had 333 g (95% confidence interval 217 to 449, p<0.001) higher mean birthweight than those who developed marasmus.
Conclusions/Significance
These data are consistent with a model suggesting that plastic mechanisms operative in utero induce potential marasmics to develop with a metabolic physiology more able to adapt to postnatal undernutrition than those of higher birthweight. Given the different mortality risks of these different syndromes, this observation is supportive of the predictive adaptive response hypothesis and is the first empirical demonstration of the advantageous effects of such a response in humans. The study has implications for understanding pathways to obesity and its cardio-metabolic co-morbidities in poor countries and for famine intervention programs.
doi:10.1371/journal.pone.0035907
PMCID: PMC3340401  PMID: 22558267
19.  Progressive, Transgenerational Changes in Offspring Phenotype and Epigenotype following Nutritional Transition 
PLoS ONE  2011;6(11):e28282.
Induction of altered phenotypes during development in response to environmental input involves epigenetic changes. Phenotypic traits can be passed between generations by a variety of mechanisms, including direct transmission of epigenetic states or by induction of epigenetic marks de novo in each generation. To distinguish between these possibilities we measured epigenetic marks over four generations in rats exposed to a sustained environmental challenge. Dietary energy was increased by 25% at conception in F0 female rats and maintained at this level to generation F3. F0 dams showed higher pregnancy weight gain, but lower weight gain and food intake during lactation than F1 and F2 dams. On gestational day 8, fasting plasma glucose concentration was higher and β-hydroxybutyrate lower in F0 and F1 dams than F2 dams. This was accompanied by decreased phosphoenolpyruvate carboxykinase (PEPCK) and increased PPARα and carnitine palmitoyl transferase-1 mRNA expression. PEPCK mRNA expression was inversely related to the methylation of specific CpG dinucleotides in its promoter. DNA methyltransferase (Dnmt) 3a2, but not Dnmt1 or Dnmt3b, expression increased and methylation of its promoter decreased from F1 to F3 generations. These data suggest that the regulation of energy metabolism during pregnancy and lactation within a generation is influenced by the maternal phenotype in the preceding generation and the environment during the current pregnancy. The transgenerational effects on phenotype were associated with altered DNA methylation of specific genes in a manner consistent with induction de novo of epigenetic marks in each generation.
doi:10.1371/journal.pone.0028282
PMCID: PMC3227644  PMID: 22140567
20.  Epigenetic gene promoter methylation at birth is associated with child’s later adiposity 
Diabetes  2011;60(5):1528-1534.
Objective
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans.
Research Design and Methods
Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5′ from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10% we related methylation status to maternal pregnancy diet and to child’s adiposity at age 9 years. Replication was sought in a second independent cohort.
Results
In cohort 1, RXRA chr9:136355885+ and eNOS chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient (β) 17% per standard deviation change in methylation (95% confidence interval (CI) 4 to 31%), P=0.009, n=64 and β=20% (9 to 32%), P<0.001, n=66, respectively) and %fat mass (β=10% (1 to 19%), P=0.023, n=64 and β=12% (4 to 20%), P=0.002, n=66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β=6% (2 to 10%) and β=4% (1 to 7%), respectively, both P=0.002, n=239).
Conclusions
Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.
doi:10.2337/db10-0979
PMCID: PMC3115550  PMID: 21471513
21.  Gene expression profiling in the Cynomolgus macaque Macaca fascicularis shows variation within the normal birth range 
BMC Genomics  2011;12:509.
Background
Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology.
Method
To explore this further, we utilised a non-human primate model Macaca fascicularis (Cynomolgus macaque) which shares with humans the same progressive history of the metabolic syndrome. Using microarray we compared tissues from neonates in the average birth weight (50-75th centile) to those of lower birth weight (5-25th centile) and studied the effect of different growth trajectories within the normal range on gene expression levels in the umbilical cord, neonatal liver and skeletal muscle.
Results
We identified 1973 genes which were differentially expressed in the three tissue types between average and low birth weight animals (P < 0.05). Gene ontology analysis identified that these genes were involved in metabolic processes including cellular lipid metabolism, cellular biosynthesis, cellular macromolecule synthesis, cellular nitrogen metabolism, cellular carbohydrate metabolism, cellular catabolism, nucleotide and nucleic acid metabolism, regulation of molecular functions, biological adhesion and development.
Conclusion
These differences in gene expression levels between animals in the upper and lower percentiles of the normal birth weight range may point towards early life metabolic adaptations that in later life result in differences in disease risk.
doi:10.1186/1471-2164-12-509
PMCID: PMC3210194  PMID: 21999700
22.  Developmental origins of health and disease: reducing the burden of chronic disease in the next generation 
Genome Medicine  2010;2(2):14.
Despite a wealth of underpinning experimental support, there has been considerable resistance to the concept that environmental factors acting early in life (usually in fetal life) have profound effects on vulnerability to disease later in life, often in adulthood. This has resulted in an unwillingness among public health decision makers to implement relatively simple approaches, based upon an understanding of developmental plasticity and intergenerational influences, to reducing the burden of disease particularly in low socioeconomic groups.
doi:10.1186/gm135
PMCID: PMC2847705  PMID: 20236494
23.  Impaired Perinatal Growth and Longevity: A Life History Perspective 
Life history theory proposes that early-life cues induce highly integrated responses in traits associated with energy partitioning, maturation, reproduction, and aging such that the individual phenotype is adaptively more appropriate to the anticipated environment. Thus, maternal and/or neonatally derived nutritional or endocrine cues suggesting a threatening environment may favour early growth and reproduction over investment in tissue reserve and repair capacity. These may directly affect longevity, as well as prioritise insulin resistance and capacity for fat storage, thereby increasing susceptibility to metabolic dysfunction and obesity. These shifts in developmental trajectory are associated with long-term expression changes in specific genes, some of which may be underpinned by epigenetic processes. This normative process of developmental plasticity may prove to be maladaptive in human environments in transition towards low extrinsic mortality and energy-dense nutrition, leading to the development of an inappropriate phenotype with decreased potential for longevity and/or increased susceptibility to metabolic disease.
doi:10.1155/2009/608740
PMCID: PMC2738951  PMID: 19746180
24.  Pre- and Postnatal Nutritional Histories Influence Reproductive Maturation and Ovarian Function in the Rat 
PLoS ONE  2009;4(8):e6744.
Background
While prepubertal nutritional influences appear to play a role in sexual maturation, there is a need to clarify the potential contributions of maternal and childhood influences in setting the tempo of reproductive maturation. In the present study we employed an established model of nutritional programming to evaluate the relative influences of prenatal and postnatal nutrition on growth and ovarian function in female offspring.
Methods
Pregnant Wistar rats were fed either a calorie-restricted diet, a high fat diet, or a control diet during pregnancy and/or lactation. Offspring then were fed either a control or a high fat diet from the time of weaning to adulthood. Pubertal age was monitored and blood samples collected in adulthood for endocrine analyses.
Results
We report that in the female rat, pubertal timing and subsequent ovarian function is influenced by the animal's nutritional status in utero, with both maternal caloric restriction and maternal high fat nutrition resulting in early pubertal onset. Depending on the offspring's nutritional history during the prenatal and lactational periods, subsequent nutrition and body weight gain did not further influence offspring reproductive tempo, which was dominated by the effect of prenatal nutrition. Whereas maternal calorie restriction leads to early pubertal onset, it also leads to a reduction in adult progesterone levels later in life. In contrast, we found that maternal high fat feeding which also induces early maturation in offspring was associated with elevated progesterone concentrations.
Conclusions
These observations are suggestive of two distinct developmental pathways leading to the acceleration of pubertal timing but with different consequences for ovarian function. We suggest different adaptive explanations for these pathways and for their relationship to altered metabolic homeostasis.
doi:10.1371/journal.pone.0006744
PMCID: PMC2727050  PMID: 19707592
25.  The nature of the growth pattern and of the metabolic response to fasting in the rat are dependent upon the dietary protein and folic acid intakes of their pregnant dams and post-weaning fat consumption 
The British journal of nutrition  2007;99(3):540-549.
The nutritional cues which induce different phenotypes from a single genotype in developing offspring are poorly understood. How well prenatal nutrient availability before birth predicts that after birth may also determine the offspring's response to later metabolic challenge. We investigated the effect of feeding pregnant rats diets containing 180 g/ kg (Control) or 90 g/ kg (PR) protein and either 1 or 5 mg/kg folic acid on growth and metabolic response to fasting in their offspring, and also the effect of diets with different fat contents (40 g/kg (Fat4) or 100g/kg (Fat10) after weaning. Offspring of dams fed the PR diet with 5 mg/kg folic acid were significantly lighter than other offspring. The PR offspring fed the Fat4 diet had lower plasma triacylglycerol (TAG) than the Control offspring, but this relationship was reversed when offspring were fed Fat10. Increasing the folic acid content of the Control or PR maternal diets induced opposing effects on plasma TAG, non-esterified fatty acids, β-hydroxybutyrate and glucose concentrations in offspring fed Fat4. The effect was accentuated in offspring fed the Fat10 diet such that these metabolites were increased in the Control offspring, but reduced in the PR offspring. These data show for the first time that maternal dietary folic acid intake alters offspring phenotype depending upon dietary protein intake, and that this effect is modified by fat intake after weaning. Prevention by increased folic acid intake of an altered metabolic phenotype by maternal protein-restriction may be at the expense of somatic growth.
doi:10.1017/S0007114507815819
PMCID: PMC2493056  PMID: 17761015
Low protein diet; fetal programming; folic acid; Growth; Metabolism

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