Intergenerational Influences on Child Development: An Epigenetic Perspective.

The link between poor maternal nutrition and suboptimal outcomes in offspring is well established, but underlying mechanisms are not well understood. Modifications to the offspring epigenome are a plausible mechanism for the transmission of intergenerational signals that could extend to effects of paternal nutrition mediated by epigenetic modifications in sperm. The epigenome is extensively remodeled in the early embryo. Attention has therefore focused on the periconceptional period as a time when differences in parental nutrition might influence the establishment of epigenetic marks in offspring. So-called "natural experiments" in The Gambia and elsewhere have highlighted loci that may be especially sensitive to periconceptional nutrition, and some are associated with health-related outcomes in later life. There is speculation that some epigenetic signals could be transmitted across multiple generations, although this would require epigenetic marks to evade epigenetic reprogramming events at conception and in primordial germ cells, and evidence for this is lacking in humans. Effects on child development spanning one or more generations could impose an intergenerational "brake" on a child's growth potential, limiting, for example, the rate at which populations can escape from stunting

Fetal programming and epigenetics

Accumulating evidence suggests that the intrauterine environment can have an impact on long-term offspring health, so-called �fetal programming�. A number of environmental stressors have been studied in humans including maternal nutrition, smoking, substance misuse and mental illness. Although various biological mechanisms are likely to underpin fetal programming effects, there has been a particular focus on epigenetic modifications as potential mediators of observed associations between early environmental exposures and later health outcomes. In this review, we give an overview of evidence supporting a role for epigenetics in fetal programming, highlighting key human and animal studies. We also discuss challenges for research in this area, along with recommendations for future work, and potential therapeutic applications

SPH Simulations of Direct Impact Accretion in the Ultracompact AM CVn Binaries

The ultracompact binary systems V407 Vul (RX J1914.4+2456) and HM Cnc (RX J0806.3+1527) - a two-member subclass of the AM CVn stars - continue to pique interest because they defy unambiguous classification. Three proposed models remain viable at this time, but none of the three is significantly more compelling than the remaining two, and all three can satisfy the observational constraints if parameters in the models are tuned. One of the three proposed models is the direct impact model of Marsh & Steeghs (2002), in which the accretion stream impacts the surface of a rapidly-rotating primary white dwarf directly but at a near-glancing angle. One requirement of this model is that the accretion stream have a high enough density to advect its specific kinetic energy below the photosphere for progressively more-thermalized emission downstream, a constraint that requires an accretion spot size of roughly 1.2x10^5 km^2 or smaller. Having at hand a smoothed particle hydrodynamics code optimized for cataclysmic variable accretion disk simulations, it was relatively straightforward for us to adapt it to calculate the footprint of the accretion stream at the nominal radius of the primary white dwarf, and thus to test this constraint of the direct impact model. We find that the mass flux at the impact spot can be approximated by a bivariate Gaussian with standard deviation \sigma_{\phi} = 164 km in the orbital plane and \sigma_{\theta} = 23 km in the perpendicular direction. The area of the the 2\sigma ellipse into which 86% of the mass flux occurs is roughly 47,400 km^2, or roughly half the size estimated by Marsh & Steeghs (2002). We discuss the necessary parameters of a simple model of the luminosity distribution in the post-impact emission region.Comment: 24 pages, 5 figures, Accepted for publication in Ap

Influence of intergenerational in utero parental energy and nutrient restriction on offspring growth in rural Gambia.

The prenatal environment can alter an individual's developmental trajectory with long-lasting effects on health. Animal models demonstrate that the impact of the early life environment extends to subsequent generations, but there is a paucity of data from human populations on intergenerational transmission of environmentally induced phenotypes. Here we investigated the association of parental exposure to energy and nutrient restriction in utero on their children's growth in rural Gambia. In a Gambian cohort with infants born between 1972 and 2011, we used multiple regression to test whether parental season of birth predicted offspring birth weight (n = 2097) or length (n = 1172), height-for-age z score (HAZ), weight-for-height z score (WHZ), and weight-for-age z score (WAZ) at 2 yr of age (n = 923). We found that maternal exposure to seasonal energy restriction in utero was associated with reduced offspring birth length (crude:-4.2 mm, P = 0.005; adjusted: -4.0 mm, P = 0.02). In contrast, paternal birth season predicted offspring HAZ at 24 mo (crude: -0.21, P = 0.005; adjusted: -0.22, P = 0.004) but had no discernible impact at birth. Our results indicate that periods of nutritional restriction in a parent's fetal life can have intergenerational consequences in human populations. Fetal growth appears to be under matriline influence, and postnatal growth appears to be under patriline intergenerational influences.-Eriksen, K. G., Radford, E. J., Silver, M. J., Fulford, A. J. C., Wegmüller, R., Prentice, A. M. Influence of intergenerational in utero parental energy and nutrient restriction on offspring growth in rural Gambia

Establishment of environmentally sensitive DNA methylation states in the very early human embryo.

The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype

Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children

Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7–9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak–nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy

DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children.

Funder: Wellcome TrustPAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and PAX8 gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that PAX8 hypomethylation at age 2 years is associated with a 21% increase in thyroid volume and an increase in free thyroxine (T4) at 5 to 8 years, the latter equivalent to 8.4% of the normal range. Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density. Furthermore, offspring PAX8 methylation was associated with periconceptional maternal nutrition, and methylation variability was influenced by genotype, suggesting that sensitivity to environmental exposures may be under partial genetic control. Together, our results demonstrate a possible link between early environment, PAX8 gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease

Environmentally sensitive hotspots in the methylome of the early human embryo

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease

Progress on the development of the Stellar X-ray Polarimeter on board of the Spectrum-X-Gamma Satellite

We present the status of the Stellar X-ray Polarimeter at November’94 devoted to measure linear polarisation from cosmic X-ray sources between 2 keV and 15 keV which will be flown on the Spectrum-X-Gamma Satellite. In particular, we focus on the performances of the engineering model after the calibrations at Lawrence Livermore Laboratories and on the improvements which have been introduced on the four flight model imaging proportional counters which are key parts of the experiment

Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort

Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: one in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic background similar to that of Gambians but with a traditional diet that is higher in choline. Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia. Our findings suggest that adequate intake levels of choline may have to be reevaluated in different ethnic groups and highlight a possible approach for identifying novel functional SNPs under the influence of dietary selective pressure