Original Article
Pre-pregnancy maternal overweight and obesity increase the risk for affective disorders in offspring
- M. Robinson, S. R. Zubrick, C. E. Pennell, R. J. Van Lieshout, P. Jacoby, L. J. Beilin, T. A. Mori, F. J. Stanley, J. P. Newnham, W. H. Oddy
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- Published online by Cambridge University Press:
- 06 September 2012, pp. 42-48
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Maternal pre-pregnancy obesity has been linked with an increased risk for negative emotionality and inattentiveness in offspring in early childhood. The aim of this study was to examine the association between maternal pre-pregnancy body mass index (BMI) and the development of affective problems (dysthymic disorder, major depressive disorder) throughout childhood and adolescence. In the Western Australian Pregnancy Cohort (Raine) Study, 2900 women provided data on their pre-pregnancy weight, and height measurements were taken at 18 weeks of gestation. BMI was calculated and categorized using standardized methods. Live-born children (n = 2868) were followed up at ages 5, 8, 10, 14 and 17 years using the Diagnostic and Statistical Manual of Mental Disorders-oriented scales of the Child Behavior Checklist (CBCL/4–18). Longitudinal models were applied to assess the relationships between maternal pre-pregnancy BMI and affective problems from age 5 through 17. There was a higher risk of affective problems between the ages of 5 and 17 years among children of women who were overweight and obese compared with the offspring of women in the healthy pre-pregnancy weight range (BMI 18.5–24.99) after adjustment for confounders, including paternal BMI. Maternal pre-pregnancy overweight and obesity may be implicated in the development of affective problems, including depression, in their offspring later in life.
Brief Report
Birth weight predicts both proteinuria and overweight/obesity in a rural population of Aboriginal and non-Aboriginal Canadians
- R. T. Oster, V. A. Luyckx, E. L. Toth
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- Published online by Cambridge University Press:
- 21 December 2012, pp. 139-145
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The risk for many chronic diseases appears to be mediated in part by birth weight. Among Aboriginal Canadians, the prevalence of end-stage renal disease and cardiovascular disease risk is disproportionately high, largely because of elevated diabetes prevalence. The relationships between birth weight (and other potential risk factors) and diabetes, hypertension, proteinuria and overweight/obesity were explored in 1439 rural Albertans (Canada), of whom 67.3% were Aboriginal. At voluntary outreach screening programs, demographic and clinical data were measured and recalled birth weights recorded. Statistical modeling using logistic regression was used to evaluate the relationships. In the final adjusted models, associations remained for low birth weight and proteinuria [odds ratio (OR) 2.36; 95% CI 1.24–4.49], as well as for high birth weight and overweight/obesity (OR 1.58; 95% CI 1.00–2.53). These findings emphasize the need to strive for healthy pregnancies, with appropriate weight gains in these and other disadvantaged populations around the world.
Original Article
Maternal undernutrition around the time of conception and embryo number each impact on the abundance of key regulators of cardiac growth and metabolism in the fetal sheep heart
- S. Lie, S. M. Sim, I. C. McMillen, O. Williams-Wyss, S. M. MacLaughlin, D. O. Kleemann, S. K. Walker, C. T. Roberts, J. L. Morrison
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- Published online by Cambridge University Press:
- 05 August 2013, pp. 377-390
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Poor maternal nutrition before and during pregnancy is associated with an increased risk of cardiovascular disease in later life. To determine the impact of maternal undernutrition during the periconceptional (PCUN: −45 days to 6 days) and preimplantation (PIUN: 0–6 days) periods on cardiac growth and metabolism, we have quantified the mRNA and protein abundance of key regulators of cardiac growth and metabolism in the left ventricle of the sheep fetus in late gestation. The cardiac protein abundance of AMP-activated protein kinase (AMPK), phospho-acetyl CoA carboxykinase (ACC) and pyruvate dehydrogenase kinase-4 (PDK-4) were decreased, whereas ACC was increased in singletons in the PCUN and PIUN groups. In twins, however, cardiac ACC was decreased in the PCUN and PIUN groups, and carnitine palmitoyltransferase-1 (CPT-1) was increased in the PIUN group. In singletons, the cardiac abundance of insulin receptor β (IRβ) was decreased in the PCUN group, and phosphoinositide-dependent protein kinase-1 (PDPK-1) was decreased in the PCUN and PIUN groups. In twins, however, the cardiac abundance of IRβ and phospho-Akt substrate 160kDa (pAS160) were increased in the PIUN group. The cardiac abundance of insulin-like growth factor-2 receptor (IGF-2R), protein kinase C alpha (PKCα) and mammalian target of rapamycin (mTOR) were decreased in PCUN and PIUN singletons and extracellular-signal-regulated kinase (ERK) was also decreased in the PIUN singletons. In contrast, in twins, cardiac abundance of IGF-2R and PKCα were increased in the PCUN and PIUN groups, phospho-ribosomal protein S6 (pRPS6) was increased in the PCUN group, and ERK and eukaryotic initiation factor 4E (eIF4E) were also increased in the PIUN fetuses. In conclusion, maternal undernutrition limited to around the time of conception is sufficient to alter the abundance of key factors regulating cardiac growth and metabolism and this may increase the propensity for cardiovascular diseases in later life.
Epigenetic changes in hypothalamic appetite regulatory genes may underlie the developmental programming for obesity in rat neonates subjected to a high-carbohydrate dietary modification
- S. Mahmood, D. J. Smiraglia, M. Srinivasan, M. S. Patel
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- 24 June 2013, pp. 479-490
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Earlier, we showed that rearing of newborn rats on a high-carbohydrate (HC) milk formula resulted in the onset of hyperinsulinemia, its persistence in the post-weaning period and adult-onset obesity. DNA methylation of CpG dinucleotides in the proximal promoter region and modifications in the N-terminal tail of histone 3 associated with the neuropeptide Y (Npy) and pro-opiomelanocortin (Pomc) genes were investigated to decipher the molecular mechanisms supporting the development of obesity in HC females. Although there were no differences in the methylation status of CpG dinucleotides in the proximal promoter region of the Pomc gene, altered methylation of specific CpG dinucleotides proximal to the transcription start site was observed for the Npy gene in the hypothalami of 16- and 100-day-old HC rats compared with their methylation status in mother-fed (MF) rats. Investigation of histone tail modifications on hypothalamic chromatin extracts from 16-day-old rats indicated decreased acetylation of lysine 9 in histone 3 (H3K9) for the Pomc gene and increased acetylation for the same residue for the Npy gene, without changes in histone methylation (H3K9) in both genes in HC rats. These findings are consistent with the changes in the levels of Npy and Pomc mRNAs in the hypothalami of HC rats compared with MF animals. Our results suggest that epigenetic modifications could contribute to the altered gene expression of the Npy and Pomc genes in the hypothalami of HC rats and could be a mechanism leading to hyperphagia and the development of obesity in adult female HC rats.
Effect of vitamin D deficiency during pregnancy on offspring bone structure, composition and quality in later life
- S. A. Lanham, C. Roberts, A. K. Habgood, S. Alexander, T. H. J. Burne, D. W. Eyles, C. N. Trueman, M. Cooper, J. J. McGrath, R. O. C. Oreffo
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- 26 July 2012, pp. 49-55
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During foetal development, calcium requirements are met as a consequence of maternal adaptations independent of vitamin D status. In contrast, after birth, dependency on vitamin D appears necessary for calcium metabolism and skeletal health. We used a rodent model (Sprague-Dawley rats), to determine if maternal vitamin D deficiency during pregnancy had a deleterious effect on bone structure at birth. Vitamin D deplete females were maintained under deplete conditions until birth of the pups, whereupon all dams were fed a vitamin D replete diet. Offspring were harvested at birth, and 140 days of age. Bones were analyzed using micro-computed tomography and strength tested to study differences in bone structure, density and strength and subjected to elemental analysis using plasma mass spectrometry to determine strontium, barium and calcium contents. Offspring from deplete mothers displayed altered trabecular parameters in the femur at birth and 140 days of age. In addition, at 140 days of age there was evidence of premature mineralization of the secondary ossification centre of the femoral head. Elemental analysis showed increased strontium uptake in the femur of the developmentally vitamin D-deficient offspring. Vitamin D depletion during development in the offspring may have a long-lasting effect, despite repletion of vitamin D from birth. This may have consequences for human health given the low vitamin D levels seen during pregnancy and current lifestyle of sun avoidance due to the risk of skin cancer.
Patterns of placental pathology in preterm premature rupture of membranes
- J. Armstrong-Wells, M. D. Post, M. Donnelly, M. J. Manco-Johnson, B. M. Fisher, V. D. Winn
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- 18 March 2013, pp. 249-255
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Inflammation is associated with preterm premature rupture of membranes (PPROM) and adverse neonatal outcomes. Subchorionic thrombi, with or without inflammation, may also be a significant pathological finding in PPROM. Patterns of inflammation and thrombosis may give insight into mechanisms of adverse neonatal outcomes associated with PPROM. To characterize histologic findings of placentas from pregnancies complicated by PPROM at altitude, 44 placentas were evaluated for gross and histological indicators of inflammation and thrombosis. Student's t-test (or Mann–Whitney U-test), χ2 analysis (or Fisher's exact test), mean square contingency and logistic regression were used when appropriate. The prevalence of histologic acute chorioamnionitis (HCA) was 59%. Fetal-derived inflammation (funisitis and chorionic plate vasculitis) was seen at lower frequency (30% and 45%, respectively) and not always in association with HCA. There was a trend for Hispanic women to have higher odds of funisitis (OR = 5.9; P = 0.05). Subchorionic thrombi were seen in 34% of all placentas. The odds of subchorionic thrombi without HCA was 6.3 times greater that the odds of subchorionic thrombi with HCA (P = 0.02). There was no difference in gestational age or rupture-to-delivery interval, with the presence or absence of inflammatory or thrombotic lesions. These findings suggest that PPROM is caused by or can result in fetal inflammation, placental malperfusion, or both, independent of gestational age or rupture-to-delivery interval; maternal ethnicity and altitude may contribute to these findings. Future studies focused on this constellation of PPROM placental findings, genetic polymorphisms and neonatal outcomes are needed.
Effects of glucocorticoid treatment given in early or late gestation on growth and development in sheep
- S. Li, D. M. Sloboda, T. J. M. Moss, I. Nitsos, G. R. Polglase, D. A. Doherty, J. P. Newnham, J. R. G. Challis, T. Braun
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- 23 January 2013, pp. 146-156
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Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40–42 days of gestation (dG). There was no consistent effect on fetal weight, or individual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.
Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns
- L. P. Bustamante-Montes, M. A. Hernández-Valero, D. Flores-Pimentel, M. García-Fábila, A. Amaya-Chávez, D. B. Barr, V. H. Borja-Aburto
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- Published online by Cambridge University Press:
- 18 April 2013, pp. 300-306
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Reproductive effects from phthalate exposure have been documented mostly in animal studies. This study explored the association between prenatal exposure to phthalate metabolites, anogenital distance and penile measurements in male newborns in Toluca, State of Mexico. A total of 174 pregnant women provided urine samples for phthalate analysis during their last prenatal visit, and the 73 who gave birth to male infants were included in the study. The 73 male newborns were weighed and measured using standardized methods after delivery. After adjusting for creatinine and supine length at birth, significant inverse associations were observed between an index of prenatal exposure to total phthalate exposure and the distance from the anus to anterior base of the penis (β = −0.191 mm per 1 μg/l, P = 0.037), penile width (β = −0.0414, P = 0.050) and stretched length (β = −0.2137, P = 0.034); prenatal exposure to mono-2-ethylhexyl phthalate exposure was associated with a reduction in the stretched length of the penis (β = −0.2604, P = 0.050). Human exposure to phthalates is a public health concern, and the system most vulnerable to its potential effects seems to be the immature male reproductive tract.
Circulating levels of the cytokines IL10, IFNγ and resistin in an obese mouse model of developmental programming
- M. A. Kępczyńska, E. T. Wargent, M. A. Cawthorne, J. R. S. Arch, J. F. O'Dowd, C. J. Stocker
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- 24 June 2013, pp. 491-498
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An infant's early developmental environment plays a pivotal role in the programming of its physiological phenotype. The identification of the factors in the maternal environment that mediate the effects of maternal obesity and diet is essential to the development of clinical intervention strategies. Maternal hyperglycaemia, hyperinsulinaemia, hypertriglyceridaemia, hyperleptinaemia and altered inflammatory cytokines concentrations are potentially important predictive factors of her future offspring's susceptibility to metabolic disease. Using a diet-induced obese mouse model, we have investigated which of these maternal factors could induce adverse metabolic programming in the offspring. Female C57Bl/6 mice were fed either laboratory chow (10% fat) or high fat diet (42% fat) for 10 weeks before mating and throughout gestation. At day 18 of pregnancy, maternal body weight, body composition and glucose tolerance were measured, as well as plasma insulin, adiponectin, RBP4, leptin, resistin and the inflammatory cytokines (IL6, IL10, IL12, IL1β, IFNγ, KC, TNF-α). At day 18 of pregnancy, high fat-fed dams were significantly heavier than the chow dams and had increased fat mass. High fat-fed dams had higher 5 h fasting blood glucose than chow dams and elevated plasma insulin. Although the obese dams had both reduced plasma adiponectin and resistin levels compared with lean dams, their plasma IL6, IL10 and IFNγ levels were all increased. High fat feeding in pregnancy leads to altered plasma concentrations of both adipokines and adipocytokines in the dam that may directly pass to the fetus and affect their development.
Reduced apoptosis in term placentas from gestational diabetic pregnancies
- L. Belkacemi, S. Kjos, D. M. Nelson, M. Desai, M. G. Ross
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- 27 March 2013, pp. 256-265
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Gestational diabetic mellitus (GDM) pregnancies have an increased risk of macrosomic infants and large placental mass, though the mechanisms explaining each of these is uncertain. We sought to evaluate the contribution of apoptosis to placental size and the expression of glucose transporters (SLC2A) in GDM pregnancies. Maternal age and pre-pregnancy body weight were documented. Newborn weights were recorded after delivery. Placentas 37–40-week gestation from control patients (no pregnancy complication) (n = 5), or with GDM (n = 5) were weighed immediately after delivery. Villous samples (4 mm diameter) were collected and divided into specimens; one was fixed in 4% paraformaldehyde for immunostaining using terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (TUNEL) and activated caspase-3. The other specimen was snap frozen in liquid nitrogen and stored at −80°C for active caspase-3, poly(ADP-ribose) polymerase (PARP), SLC2A1 and SLC2A3 gene expression analysis. Our results showed that maternal age and pre-pregnancy body weight were significantly higher in the GDM group when compared with those from the controls (P < 0.05). The mean neonatal birth weight and placenta weight were significantly higher in the GDM group compared with that from the controls (P < 0.05). The apoptotic index of placentas (0.05 ± 0.01 v. 0.17 ± 0.04, P < 0.04), active caspase-3 polypeptide fragments and PARP protein were significantly decreased in GDM placentas as compared with controls. Further, the level of placental SLC2A1 protein expression was ∼3-fold higher in GDM placentas. Our results suggest that reduced apoptosis in GDM placentas may contribute to increased placental tissue, which together with enhanced SLC2A1 expression, could play a role in fetal macrosomia.
Does the developmental plasticity hypothesis have application to Irish Travellers? Findings from the all Ireland Traveller Health Study birth cohort 2008–2011
- N. A. Hamid, P. Fitzpatrick, A. Rowan, C. McGorrian, L. Daly, C. C. Kelleher
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- 30 April 2013, pp. 307-316
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There is little record of birth weight of Irish Travellers, a minority group in Ireland. Travellers are known to have higher rate of adult chronic disease and to be exposed to life-long disadvantage. The aim of this study was to establish whether the birth weight and infant mortality rate patterns in Ireland's Travellers were consistent with the developmental plasticity hypothesis. A 1-year follow-up birth cohort study was conducted with linkage data from maternity hospital records of Traveller infants born on the island of Ireland over a 12-month period to self-identifying Traveller and general Irish population mothers from the Lifeways Cross-Generation Cohort Study. The main outcome measure was the rate of birth weight <3000 g in a cohort of Traveller children. There were 987 confirmed Traveller births, 500 of whose mothers consented to linkage to their records. A social gradient was observed in the distribution of birth weight in the general population and Traveller infants constituted the highest proportion of all social classes in the birth weight range of 3 kg or less (16.3%). There was a high rate of persistent smoking among Traveller mothers (53%). After adjustment for smoking and alcohol consumption in pregnancy, the birth weight differential persisted (OR 3.5, 95% CI 1.4–8.1). Infant mortality rate at 12.0/1000 births (95% CI 5.5–19.7) was almost four times that of the general population. This analysis confirms Travellers had a greater than expected incidence of low birth weight and high infant mortality with high rates of premature adult chronic diseases from all causes already demonstrated previously.
Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation
- S. Zhang, O. Williams-Wyss, S. M. MacLaughlin, S. K. Walker, D. O. Kleemann, C. M. Suter, J. L. Morrison, L. Molloy, J. E. Cropley, C. T. Roberts, I. C. McMillen
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- Published online by Cambridge University Press:
- 30 August 2013, pp. 391-401
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Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo–pituitary–adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of ‘periconceptional’ undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and ‘early preimplantation’ undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11β-hydroxysteroid dehydrogenase type 1 and 2 (11βHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136–138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11βHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.
Infant BMI trajectories are associated with young adult body composition
- M. M. Slining, A. H. Herring, B. M. Popkin, E. J. Mayer-Davis, L. S. Adair
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- 10 August 2012, pp. 56-68
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The dynamic aspect of early life growth is not fully captured by typical analyses, which focus on one specific time period. To better understand how infant and young child growth relate to the development of adult body composition, the authors characterized body mass index (BMI) trajectories using latent class growth analysis (LCGA) and evaluated their association with adult body composition. Data are from the Cebu Longitudinal Health and Nutrition Survey, which followed a birth cohort to age 22 years (n = 1749). In both males and females, LCGA identified seven subgroups of respondents with similar BMI trajectories from 0 to 24 months (assessed with bimonthly anthropometrics). Trajectory groups were compared with conventional approaches: (1) accelerated growth between two time points (0–4 months), (2) continuous BMI gain between two points (0–4 months and 0–24 months) and (3) BMI measured at one time point (24 months) as predictors of young adult body composition measures. The seven trajectory groups were distinguished by age-specific differences in tempo and timing of BMI gain in infancy. Infant BMI trajectories were better than accelerated BMI gain between 0 and 4 months at predicting young adult body composition. After controlling for BMI at age 2 years, infant BMI trajectories still explained variation in adult body composition. Using unique longitudinal data and methods, we find that distinct infant BMI trajectories have long-term implications for the development of body composition.
Polymorphisms in genes within the IGF-axis influence antenatal and postnatal growth
- P. G. Parmar, J. A. Marsh, H. Rob Taal, M. Kowgier, A. G. Uitterlinden, F. Rivadeneira, L. Briollais, J. P. Newnham, A. Hofman, S. J. Lye, E. A. P. Steegers, C. M. van Duijn, L. J. Palmer, V. W. V. Jaddoe, C. E. Pennell
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- Published online by Cambridge University Press:
- 24 October 2012, pp. 157-169
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Two pregnancy cohorts were used to investigate the association between single-nucleotide polymorphisms (SNPs) in genes within the insulin-like growth factor (IGF)-axis and antenatal and postnatal growth from birth to adolescence. Longitudinal analyses were conducted in the Raine pregnancy cohort (n = 1162) using repeated measures of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) from 18 to 38 weeks gestation and eight measures of postnatal height and weight (1–17 years). Replications of significant associations up to birth were undertaken in the Generation R Study (n = 2642). Of the SNPs within the IGF-axis genes, 40% (n = 58) were associated with measures of antenatal growth (P ⩽ 0.05). The majority of these SNPs were in receptors; IGF-1R (23%; n = 34) and IGF-2R (13%; n = 9). Fifteen SNPs were associated with antenatal growth (either AC or HC or FL) in Raine (P ⩽ 0.005): five of which remained significant after adjusting for multiple testing. Four of these replicated in Generation R. Associations were identified between 38% (n = 55) of the IGF-axis SNPs and postnatal height and weight; 21% in IGF-1R (n = 31) and 9% in IGF-2R (n = 13). Twenty-six SNPs were significantly associated with both antenatal and postnatal growth; 17 with discordant effects and nine with concordant effects. Genetic variants in the IGF-axis appear to play a significant role in antenatal and postnatal growth. Further replication and new analytic methods are required in order to better understand this key metabolic pathway integrating biologic knowledge about the interaction between IGF-axis components.
Early origins of longevity: prenatal exposures to food shortage among early Utah pioneers
- H. A. Hanson, K. R. Smith
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- 29 November 2012, pp. 170-181
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Undernutrition during critical or sensitive prenatal periods may ‘program’ the fetus for increased chronic disease and mortality in later life. Using birth cohorts that were or were not exposed to severe food shortage in Utah in the mid-19th century, this study examines how in utero exposure to undernutrition is associated with mortality after age 50. The Utah Population Database is used to identify 1392 prenatally exposed individuals and 29,022 individuals from subsequent, unexposed birth cohorts. Gompertz hazards with parametric frailty show that males born between April and June of the famine period (and hence exposed during critical periods in utero during the winter months) have higher mortality risks compared with post-famine cohorts. Alternative Cox non-proportional hazard models suggest that females born during the same period have higher initial mortality risks (starting at age 50) that decline over time creating a mortality crossover with unexposed women at approximately age 70, a result not found for men. An ancillary sibling analysis that uses shared frailty survival models to compare individuals with prenatal exposure to undernutrition to their younger (post-famine) same-sex siblings finds no significant differences in adult mortality for males but the pattern for females support the findings from the previous analysis. Although findings are sensitive to model choice, this study presents evidence that is consistent with an association between undernutrition in utero and adult mortality, shows that effects may be sensitive to the duration and gestational period of exposure, and illustrates the differential exposure effects between genders.
High altitude hypoxia and blood pressure dysregulation in adult chickens
- E. A. Herrera, C. E. Salinas, C. E. Blanco, M. Villena, D. A. Giussani
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- 19 September 2012, pp. 69-76
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Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measured in vivo in conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2 and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.
Interplay between polymorphisms and methylation in the H19/IGF2 gene region may contribute to obesity in Mexican-American children
- M. A. Hernández-Valero, J. Rother, I. Gorlov, M. Frazier, O. Gorlova
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- 20 September 2013, pp. 499-506
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Imprinted genes often affect body size-related traits such as weight. However, the association of imprinting with obesity, especially childhood obesity, has not been well studied. Mexican-American children have a high prevalence, approaching 50%, of obesity and/or overweight. In a pilot study of 75 Mexican-American children, we analyzed the relationships among obese/overweight status, methylation status and single-nucleotide polymorphism (SNP) status at a CpG site in a differentially methylated region (DMR) of the imprinted H19/IGF2 locus. We observed a significant difference in SNP rs10732516 frequency between boys and girls among the overweight and obese children but not among the lean children. We also found that children with lower methylation of the polymorphic CpG site (CpG4) in the H19 DMR had higher birth weights than did children with higher methylation (P = 0.04). Our results suggest that CpG4 methylation status may be associated with childhood obesity in Mexican-American children in a sex-specific manner.
The effect of antenatal factors and postnatal growth on serum adiponectin levels in children
- M. S. Boyne, D. S. Thompson, C. Osmond, R. A. Fraser, M. M. Thame, C. Taylor-Bryan, S. Soares-Wynter, T. E. Forrester
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- Published online by Cambridge University Press:
- 31 May 2013, pp. 317-323
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Low levels of serum adiponectin (i.e. hypoadiponectinaemia) are a marker of cardiometabolic risk in overweight children. It is not clear whether early-life factors may play a role in the development of hypoadiponectinaemia. We investigated whether antenatal factors and postnatal growth are associated with childhood adiponectin levels. This was an observational study in a birth cohort (Vulnerable Windows Cohort Study). Anthropometry was measured at birth, at 6 weeks, every 3 months up to 2 years and then every 6 months. Fasting glucose, insulin, lipids and adiponectin were measured at a mean age 11.5 years. Data on 323 children were analysed with age- and sex-adjusted multivariate analyses. The sizes of mother, placenta, fetus and newborn were not significantly associated with adiponectin levels. Current weight, body mass index (BMI), fat mass, waist circumference, glucose, insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)], triglycerides and systolic blood pressure were inversely related to adiponectin (P < 0.05). Faster growth in BMI during late infancy and childhood was associated with lower adiponectin levels (P < 0.05). After adjusting for current waist circumference, faster growth in BMI during early infancy was positively associated with adiponectin (P < 0.01). Faster growth in BMI during childhood was inversely associated (P < 0.001). These associations were similar after adjusting for HOMA-IR. We concluded that antenatal factors are not determinants of childhood adiponectin levels. Faster growth in BMI during infancy is associated with higher levels, whereas faster rates during childhood are associated with hypoadiponectinaemia. Hypoadiponectinaemia is a marker of a more adverse cardiometabolic profile in Afro-Caribbean children.
Elevated plasma norepinephrine inhibits insulin secretion, but adrenergic blockade reveals enhanced β-cell responsiveness in an ovine model of placental insufficiency at 0.7 of gestation
- A. R. Macko, D. T. Yates, X. Chen, A. S. Green, A. C. Kelly, L. D. Brown, S. W. Limesand
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- Published online by Cambridge University Press:
- 10 April 2013, pp. 402-410
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In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced β-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were threefold greater compared with age-matched controls, but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory β-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P < 0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P < 0.05) basal blood oxygen content, plasma glucose, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 1.08 ± 0.06 ng/ml; P < 0.05). ADR-block increased GSIS in PI fetuses (1.19 ± 0.11 ng/ml; P < 0.05) but decreased GSIS in controls (0.86 ± 0.02 ng/ml; P < 0.05). Similarly, GPAIS was 44% lower (P < 0.05) in PI fetuses than in controls, and ADR-block increased (P < 0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations, and that compensatory β-cell stimulus-secretion responsiveness is present before IUGR.
Exposures in early life: associations with DNA promoter methylation in breast tumors
- M.-H. Tao, C. Marian, P. G. Shields, N. Potischman, J. Nie, S. S. Krishnan, D. L. Berry, B. V. Kallakury, C. Ambrosone, S. B. Edge, M. Trevisan, J. Winston, J. L. Freudenheim
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- Published online by Cambridge University Press:
- 10 December 2012, pp. 182-190
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There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case–control study. Promoter methylation of E-cadherin, p16 and RAR-β2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case–case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case–case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15–6.82, for ⩽2.5 v. 2.6–2.9 kg); higher adult height with RAR-β2 methylation (OR = 3.34, 95% CI, 1.19–9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14–6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.