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Funder: Rural and Environment Science and Analytical Services Division; doi: http://dx.doi.org/10.13039/100011310, Epigenetic imprinting is important for neurogenesis and brain function. Hippocampal volumes and brain hyperintensities in late life have been associated with early life circumstances. Epigenetic imprinting may underpin these associations. Methylation was measured at 982 sites in 13 imprinted locations in blood samples from a longitudinal cohort by bisulphite amplicon sequencing. Hippocampal volumes and hyperintensities were determined at age 64y and 72y using MRI. Hyperintensities were determined in white matter, grey matter and infratentorial regions. Permutation methods were used to adjust for multiple testing. At 64y, H19/IGF2 and NESPAS methylation predicted hippocampal volumes. PEG3 predicted hyperintensities in hippocampal grey matter, and white matter. GNASXL predicted grey matter hyperintensities. Changes with age were predicted for hippocampal volume (MEST1, KvDMR, L3MBTL, GNASXL), white matter (MEST1, PEG3) and hippocampal grey matter hyperintensities (MCTS2, GNASXL, NESPAS, L3MBTL, MCTS2, SNRPN, MEST1). Including childhood cognitive ability, years in education, or socioeconomic status as additional explanatory variables in regression analyses did not change the overall findings. Imprinting methylation in multiple genes predicts brain structures, and their change over time. These findings are potentially relevant to the development of novel tests of brain structure and function across the life-course, strategies to improve cognitive outcomes, and our understanding of early influences on brain development and function.

[This corrects the article DOI: 10.1371/journal.pone.0211799.].

Purpose of review Epigenetics has emerged in recent years as one of the most important biological mechanisms linking exposures across the life course to long-term health. This article reviews recent developments in our understanding of the metabolic and genetic determinants of epigenetic variation in human populations. Recent findings Epigenetic status is influenced by a range of environmental exposures, including diet and nutrition, social status, the early emotional environment, and infertility and its treatment. The period around conception is particularly sensitive to environmental exposures with evidence for effects on epigenetic imprinting within the offspring. Epigenetic status is also influenced by genotype, and genetic variation in methylene tetrahydrofolate reductase, and the DNA methytransferase and ten-eleven translocation methylcytosine dioxygenase proteins has been linked to the epigenetic status, biological function and disease. Summary Epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists within. It offers the potential for modification of adverse epigenetic states resulting from events/exposures at earlier life stages. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and health in current and future generations.

Cognitive abilities vary among people. About 40–50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) – the ability to reason in novel situations – and general crystallized intelligence (gC) – the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF–gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation. publishedVersion

STUDY QUESTION Is DNA methylation in buccal cell DNA from children born following IVF (in vitro fertilization) and ICSI (intra-cytoplasmic sperm injection) different from that of spontaneously conceived children? SUMMARY ANSWER DNA methylation in the imprinted gene, small nuclear ribonucleoprotein polypeptide N (SNRPN), was higher in children conceived by ICSI and in those born to women with the longest duration of infertility regardless of the method of conception. WHAT IS KNOWN ALREADY Fertility treatment is associated with a small but significant increase in the risk of a range of adverse obstetric outcomes, birth defects and longer term sequelae, but the biological basis for this is unknown. A growing evidence base suggests that epigenetics may play a role in subfertility and the link between fertility and health. STUDY DESIGN, SIZE, DURATION In this retrospective cohort study of children born between 2002 and 2008, we measured DNA methylation in paternally expressed gene 3 (PEG3), insulin-like growth factor II (IGF2), SNRPN, long interspersed nuclear element 1 (LINE1) and the insulin gene (INS) in buccal cell DNA from children born following IVF (n = 49) and ICSI (n = 20) and compared them with a matched spontaneous conception group (n = 86). PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were identified from the Aberdeen Maternity and Neonatal Databank and IVF and ICSI pregnancies were matched to spontaneous conception pregnancies on year of birth and maternal age at delivery. Only singleton pregnancies following fresh embryo transfer were included. DNA methylation was determined by pyrosequencing. Regression with adjustment for covariates was used to determine the effect of infertility on offspring DNA methylation. MAIN RESULTS AND THE ROLE OF CHANCE SNRPN methylation in the offspring was linked to fertility treatment in the parents. This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (1.03%; 95% CI 0.10, 1.97; P = 0.031), ICSI versus standard IVF (1.13%; 95% CI 0.04, 2.23; P = 0.043) and ICSI versus standard IVF and spontaneous conception (1.05; 95% CI 0.15, 1.94; P = 0.023). In all comparisons, the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (0.18% per year of infertility; 95% CI 0.02, 0.33; P = 0.026) and after excluding ICSI cases (0.21% per year of infertility; 95% CI 0.04, 0.37; P = 0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (0.77% per year; 95% CI 0.49, 1.05; P < 0.001). Methylation in the INS gene decreased significantly over the same period (−0.46% per year; 95% CI −0.89, −0.03; P = 0.035). There was no evidence from this cross-sectional data that methylation within the imprinted genes changed over the first 7 years of life. LIMITATIONS, REASONS FOR CAUTION The ICSI sample size was limited but the groups were carefully selected and well matched and the SNRPN findings were consistent across different outcomes. WIDER IMPLICATIONS OF THE FINDINGS The results of this study provide support for a role for epigenetics, and imprinting in particular, in fertility. The specific changes point to possible long-term consequences of fertility treatment for the health and fertility of future generations. STUDY FUNDING/COMPETING INTEREST(S) The authors report no conflict of interest in relation to this work. Funding was provided by the University of Aberdeen and the Scottish Government.

The aim of this review is to summarize recent evidence on the importance of individual long chain polyunsaturated fatty acid (LCPUFA) to the developing fetus and the maternal dietary requirement for these.Large-scale randomized controlled trials and innovative genetic and stable isotope studies are providing new insights in this field.Large randomized controlled trials of LCPUFA supplementation in pregnancy suggest that higher n-3 LCPUFA intake reduces the risk of preterm birth and increases the length of gestation, with secondary effects on birth weight. There is little evidence of an effect on postnatal visual function and cognition, but interpretation is complicated by maternal metabolic adaptations and adipose tissue status in the newborn. The links between polymorphisms in the FADS genes and tissue fatty acid composition suggest that LCPUFA synthesis influences overall availability. Stable isotope studies have also demonstrated the capacity for LCPUFA synthesis in pregnancy, the fact that n-6 synthesis is greater than n-3, metabolic channeling of individual fatty acids to different fates, and selective placental transfer. Studies linking FADS genotype to cognition imply that n-3 LCPUFA synthesis could have an effect on infant cognition, but more large-scale genetic studies are needed.

Background: Epigenetic regulation of imprinted genes and transposable elements has been implicated in human disease and may be affected by maternal diet. Objective: The objective was to determine the effect on offspring epigenetic status of nutritional and genetic factors that influence folate exposure in pregnancy. Design: We measured folate intake from diet, the use of folic acid supplements and the period of consumption, maternal and cord red blood cell (RBC) folate, and genotypes for 5 methylation cycle enzymes in a prospective cohort study of pregnancies in the United Kingdom between 2000 and 2006. We related these to offspring methylation status within 3 maternally methylated imprinted genes: paternally expressed gene 3 (PEG3), insulin-like growth factor 2 (IGF2), and small nuclear ribonucleoprotein polypeptide N, and the long interspersed nuclear element 1 (LINE-1) in genomic DNA extracted from whole blood in 913 pregnancies. Results: Supplement use after 12 wk of gestation was associated with a higher level of methylation in IGF2 (+0.7%; 95% CI: 0.02, 1.4; P = 0.044) and reduced methylation in both PEG3 (20.5%; 95% CI: 20.9, 20.1; P = 0.018) and LINE-1 (20.3%; 95% CI: 20.6, 20.04; P = 0.029). The same pattern was observed in relation to RBC folate in the cord blood at birth: IGF2 (P = 0.038), PEG3 (P , 0.001), and LINE-1 (P , 0.001). LINE-1 methylation was related to maternal RBC folate (P = 0.001) at 19 wk. No effect of supplement use up to 12 wk (current recommendation) was found. Conclusions: Folic acid use after 12 wk of gestation influences offspring repeat element and imprinted gene methylation. We need to understand the consequences of these epigenetic effects. Am J Clin Nutr 2013;97:94‐9.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP - rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog) - had a genome-wide significant association with cognitive ageing (P=2.5 × 10 -8). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10 -6). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10 -8; females, P=1.66 × 10 -11; males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10 -11) and TOMM40 (rs11556505; P=2.45 × 10 -8) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear. © 2014 Macmillan Publishers Limited.

The aims of the present study were to determine compliance with current advice on vitamin D and to assess the influence of season, dietary intake, supplement use and deprivation on vitamin D status in pregnant mothers and newborns in the north of Scotland where sunlight exposure is low. Pregnant women (n 1205) and their singleton newborns were studied in the Aberdeen Maternity Hospital (latitude 57°N) between 2000 and 2006. Plasma 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 were measured at 19 weeks of gestation in mothers and at delivery in newborns. During pregnancy, 21·0 (95 % CI 18·5, 23·5) % of women took vitamin D supplements. The median intake was 5 μg/d and only 0·6 (95 % CI 0·1, 1·0) % took the recommended 10 μg/d. Supplement use, adjusted for season, dietary intake and deprivation, significantly increased maternal 25-hydroxyvitamin D (25(OH)D) by 10·5 (95 % CI 5·7, 15·2) nmol/l (PPv. 23 (95 % CI 20, 26) %). More should be done to promote vitamin D supplement use in pregnancy but the critical importance of endogenous vitamin D synthesis, and known adaptations of fat metabolism specific to pregnancy, suggest that safe sun advice may be a useful additional strategy, even at high latitude.

General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted B1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence. Molecular Psychiatry advance online publication, 9 August 2011; doi:10.1038/mp.2011.85

The motivation of the project was to investigate the use of oxygen-challenge magnetic resonance imaging (OC-MRI) as a method of diagnosing foetal growth restriction. Foetal growth restriction is associated with restricted foetal oxygen supply and is also associated with increased risks of perinatal mortality and morbidity, and a number of serious and chronic health problems. Measurements of T2* relaxation time, an MRI parameter which increases with blood oxygenation, were made in the right lobe of the foetal liver in 80 singleton pregnancies, before and after the mother breathed oxygen. The groups consisted of 41 foetuses with normal growth and 39 with apparent growth restriction. The mean +/- SD gestational age at scanning was 35 +/- 3 weeks. Changes in foetal liver T2* on maternal oxygen breathing showed no significant difference between the groups therefore the OC-MRI protocol used in this study has no value in the diagnosis of foetal growth restriction. A secondary finding was that a significant positive correlation of T2* change with gestational age was observed. Future studies on the use of oxygen-challenge MRI to investigate foetal growth restriction may therefore need to control for gestational age at the time of MR scanning in order to observe any underlying foetal growth-related effects.

Deposition of fat in the fetus increases exponentially with gestational age, reaching its maximal rate—around 7 g/day or 90% of energy deposition—at term. In late pregnancy, many women consuming contemporary Western diets may not be able to meet the fetal demand for n-3 long chain polyunsaturated fatty acids (LCPUFAs) from the diet alone. Numerous mechanisms have evolved to protect human offspring from extreme variation or deficiency in the maternal diet during pregnancy. Maternal adipose tissue is an important source of LCPUFA. Temporal changes in placental function are synchronized with maternal metabolic and physiological changes to ensure a continuous supply of n-3 and n-6 LCPUFA-enriched fat to the fetus. LCPUFA storage in fetal adipose tissue provides an important source of LCPUFA during the critical first months of postnatal life. An appreciation of these adaptations is important in any nutritional strategy designed to improve the availability of fatty acids to the fetus.

Deprivation is associated with poor pregnancy outcome but the role of nutrition as a mediating factor is not well understood. We carried out a prospective cohort study of 1461 singleton pregnancies in Aberdeen, UK during 2000–6. We measured nutrient intake and supplement use, B vitamin and homocysteine status, birth weight, gestational age, neonatal treatment and socio-economic deprivation status. Women in the most deprived deciles were approximately 6 years younger and half as likely to take folic acid supplements periconceptually as the least deprived mothers. Deprivation was associated with low blood folate, high homocysteine and diets low in protein, fibre and many of the vitamins and minerals. The diets of the more deprived women were also characterised by low intakes of fruit, vegetables and oily fish and higher intakes of processed meat, fried potatoes, crisps and snacks. Deprivation was related to preterm birth (OR 1·14 (95 % CI 1·03, 1·25); P = 0·009) and whether the baby required neonatal treatment (OR 1·07 (95 % CI 1·01, 1·14); P = 0·028). Low birth weight was more common in women consuming diets low in vitamin C (OR 0·79 (95 % CI 0·64, 0·97); P = 0·028), riboflavin (OR 0·77 (95 % CI 0·63, 0·93); P = 0·008), pantothenic acid (OR 0·79 (95 % CI 0·65, 0·97); P = 0·023) and sugars (OR 0·78 (95 % CI 0·64, 0·96); P = 0·017) even after adjustment for deprivation index, smoking, marital status and parity. Deprivation in pregnancy is associated with diets poor in specific nutrients and poor diet appears to contribute to inequalities in pregnancy outcome. Improving the nutrient intake of disadvantaged women of childbearing age may potentially improve pregnancy outcome.

Despite a great deal of research effort there is still considerable uncertainty surrounding the importance of the B-vitamins in health and disease. This continuing uncertainty is partly a result of the difficulty of measuring intake, confounding in observational studies and the very large numbers required to evaluate primary prevention in randomised controlled trials. Consequently, genetic data are increasingly being used to infer nutritional effects on health and even in the formulation of nutrition policy using the approach of ‘mendelian randomisation’. Genetic information has already contributed greatly to the understanding of B-vitamin metabolism and the heterogeneity of responses to intake. It has the potential to provide further nutritional insights and to assist in the elucidation of causal mechanisms, but it is important that genetic data is not viewed as an alternative to nutritional information, both are necessary when addressing nutritional problems. Similarly, the interpretation of nutrient and biomarker status in some experimental designs may require knowledge of genotype. Formal tests of gene–gene and gene–nutrient interaction are of limited value in nutritional studies and the formulation of policy. Graphical representation of diet–genotype–health data greatly assists in the elucidation of the nature of genetic effects, their interaction with nutrition and the implications for nutrition policy.

Background Altered DNA methylation of imprinted genes has been implicated in a range of cancers. Imprinting is established early in development, and some are maintained throughout the life course in multiple tissues, providing a plausible mechanism linking known early life factors to cancer risk. This study investigated methylation status of seven imprinted differentially methylated regions—PLAGL1/ZAC1, H19-ICR1, IGF2-DMR2, KvDMR-ICR2, RB1, SNRPN-DMR1 and PEG3—in blood samples from 189 women with the most common type of invasive breast cancer (invasive ductal carcinoma—IDC), 41 women with in situ breast cancer (ductal carcinoma in situ—DCIS) and 363 matched disease-free controls. Results There was no evidence that imprinted gene methylation levels varied with age (between 25 and 87 years old), weight or height. Higher PEG3 methylation was associated with an elevated risk of IDC (odds ratio (OR) 1.065; 95 % confidence interval (CI) 1.002, 1.132; p = 0.042) and DCIS (OR 1.139; 95 % CI 1.027, 1.263; p = 0.013). The effect was stronger when in situ and invasive breast cancer were combined (OR 1.079; 95 % CI 1.020, 1.142; p = 0.008). DCIS breast cancer risk increased with higher KvDMR-ICR2 methylation (OR 1.395; 95 % CI 1.190, 1.635; p

Summary Background There is a need to understand what affects the success of in-vitro fertilisation (IVF) and the rate of resulting twin births so that pregnancy rates can be improved and multiple gestations avoided. Our aim was to assess the role of B vitamins and genetics. Methods We did a prospective cohort study of 602 women undergoing fertility treatment. We assessed intake of folate and vitamin B12 with a questionnaire and measured their plasma and red-blood-cell concentrations by radioimmunoassay. We measured five B-vitamin-related gene variants in women who received treatment and in 932 women who conceived naturally. Findings The likelihood of a twin birth after IVF rose with increased concentrations of plasma folate (1·52, 1·01–2·28; p=0·032) and red-cell folate (1·28, 1·00–1·65; p=0·039). There was no association between folate and vitamin B12 levels and likelihood of a successful pregnancy. Women homozygous for the 1298 CC variant of methylenetetrahydro-folate reductase ( MTHFR ), rather than the AA variant, were less likely to produce a livebirth after IVF (0·24, 0·08–0·71; p=0·003) or to have had a previous pregnancy (0·42, 0·21–0·81; p=0·008). Interpretation Our findings suggest that MTHFR genotype is linked to a woman's potential to produce healthy embryos (possibly through interaction with genes related to DNA methylation). In women likely to have a successful IVF pregnancy, high folate status increases the likelihood of twin birth after multiple embryo transfer. Proposals to fortify the UK diet with folic acid could lead to an increase in the number of twins born after IVF.

Twins can be used to investigate the biological basis for observed associations between birth weight and later disease risk, as they experiencein uterogrowth restriction compared with singletons, which can differ in magnitude within twin pairs despite partial or total genetic identity. In the present study, sixty monozygotic and seventy-one dizygotic same-sex twin pairs aged 19–50 years and eighty-nine singleton controls matched for age, gestational age, sex, maternal age and parity were recruited from an obstetric database. Associations between fasting lipid levels and birth weight were assessed by linear regression with adjustment for possible confounding factors. Twins were significantly lighter at birth but were not significantly different in adult height, weight or lipid levels from the singleton controls. There was a significant inverse association between birth weight and both total and LDL-cholesterol levels among singleton controls (−0·53mmol/l per kg (95% CI −0·97, −0·09),P=0·02 and −0·39mmol/l per kg (95% CI −0·76, −0·02),P=0·04, respectively), but there was no significant association between birth weight and lipid levels in either unpaired or within-pair analysis of twins. The results suggest that thein uterogrowth restriction and early catch-up growth experienced by twins does not increase the risk of an atherogenic lipid profile in adult life.

The ActiReg® (PreMed AS, Oslo, Norway) system is unique in using combined recordings of body position and motion alone or combined with heart rate (HR) to calculate energy expenditure (EE) and express physical activity (PA). The ActiReg® has two pairs of position and motion sensors connected by cables to a battery-operated storage unit fixed to a waist belt. Each pair of sensors was attached by medical tape to the chest and to the front of the right thigh respectively. The collected data were transferred to a personal computer and processed by a dedicated program ActiCalc®. Calculation models for EE with and without HR are presented. The models were based on literature values for the energy costs of different activities and therefore require no calibration experiments. The ActiReg® system was validated against doubly labelled water (DLW) and indirect calorimetry. The DLW validation demonstrated that neither EE calculated from ActiReg® data alone (EEAR) nor from combined ActiReg® and HR data (EEAR–HR) were statistically different from DLW results. The EEAR procedure causes some underestimation of EE >11 MJ corresponding to a PA level >2·0. This underestimation is reduced by the EEAR–HR procedure. The objective recording of the time spent in different body positions and at different levels of PA may be useful in studies of PA in different groups and in studies of whether recommendations for PA are being met. The comparative ease of data collection and calculation should make ActiReg® a useful instrument to measure habitual PA level and EE.

Objective To evaluate the usefulness of ponderal index (PI) and related indices of weight and length in identifying asymmetric growth, body thinness and organ asymmetry associated with IUGR. Design Cross sectional study. Setting Aberdeen Maternity Hospital. Population The population includes term (≥37 weeks) singleton live births (n= 53,934) between 1986 and 1996, ultrasound measurements in 2522 pregnancies, 712 unselected term pregnancies in 1979/1980 and stillbirths (24–36 weeks) between 1986 and 1995 where the fetus was diagnosed as suffering from acute (n= 73) or chronic (n= 30) anoxic death. Methods The strength of association between direct measures of IUGR and various indices of weight and length was determined by linear and multiple stepwise linear regression. Main outcome measures Weight, length, PI and skinfold thicknesses (triceps, biceps, flank thighs, back) were measured at birth. Abdominal circumference, biparietal diameter and femur length were measured by ultrasound at ≥37 weeks. Ratio of liver, heart and kidney to brain were measured in stillbirths. Results Weight alone was a better predictor of skinfold thickness, abdominal circumference and the ratio of abdominal circumference to biparietal diameter than weight divided by length raised to the power 1, 2, 3 (PI), 4 or 5. The inclusion of gestational age made little difference to the predictive ability of weight for these full term births. Weight, but not PI, was significantly different between the two groups of stillborn fetuses (chronic and acute), which had significantly different (P < 0.001) organ ratios. Conclusion Body weight alone was a better predictor of anthropometric ratios, organ asymmetry and measures of thinness at birth thought to be associated with IUGR than the PI. The inclusion of a length term generally reduced the predictive ability with the highest powers resulting in the poorest prediction.

More than 90 per cent of the fat deposition in the fetus occurs in the last 10 weeks of pregnancy during which it increases exponentially to reach a rate of accretion of around 7g/day close to term. All of the n -3 and n -6 fatty acid structure acquired by the fetus has to cross the placenta and fetal blood is enriched in long chain polyunsaturated fatty acids (LCPUFA) relative to the maternal supply. The placenta may regulate its own fatty acid substrate supply via the action of placental leptin on maternal adipose tissue. Fatty acids cross the microvillous and basal membranes by simple diffusion and via the action of membrane bound and cytosolic fatty acid binding proteins (FABPs). The direction and magnitude of fatty acid flux is mainly dictated by the relative abundance of available binding sites. The fatty acid mix delivered to the fetus is largely determined by the fatty acid composition of the maternal blood although the placenta is able to preferentially transfer the important PUFA to the fetus as a result of selective uptake by the syncytiotrophoblast, intracellular metabolic channelling of individual fatty acids, and selective export to the fetal circulation. Placental FABP polymorphisms may affect these processes. There is little evidence to suggest that placental delivery of fatty acids limits normal fetal growth although the importance of the in utero supply may be to support post-natal development as most of the LCPUFA accumulated by the fetus is stored in the adipose tissue for use in early post-natal life.

The role of the placenta in controlling the supply of fatty acids to the fetus was investigated in term placentas from non-smokers (n5), smokers (>ten cigarettes/d;n5) and after addition of ethanol at 2 mg/ml (n4). The maternal side was of the placenta was perfusedex vivofor 90 min with a physiological mixture of fatty acids and fatty acid:human albumin ratio. There was no effect of smoking on the transfer of linoleic (LA, 18 : 2n-6), α-linolenic (αLN, 18 : 3n-3), arachidonic (AA, 20 : 4n-6) or docosahexaenoic acid (DHA, 22 : 6n-3), expressed per perfused area (calculated from H218O exchange). However, the presence of ethanol in the perfusate at a concentration of 2 mg/ml significantly reduced (Pn-3 polyunsaturated fatty acids, αLN and DHA. This specific effect of ethanol on αLN and DHA also resulted in an altered selectivity for transfer of individual fatty acids. In the non-smoking control group the placenta selectively transferred polyunsaturated fatty acids to the fetus in the order DHA>AA>αLN>LA. The order of selectivity was unaltered in placentas from smokers, but the addition of ethanol to the perfusion medium altered the order of selectivity to AA>αLN>LA>DHA. The presence of ethanol in the perfusate was also associated with a significant reduction (P218O. These results suggest that the presence of ethanol at a concentration of 2 mg/ml may reduce the availability of polyunsaturated fatty acids to the developing fetus.

The objective of this study was to determine whether the ability of the human placenta to transfer glucose and fatty acids is related to normal fetal growth. The intrinsic nutrient transport capacity of the placenta was measured under standardized conditions during in vitro perfusion of 30 human term placentas and related to birth weight (range 2640–4640g), birth weight centile (8th–99th), ponderal index (2.43–3.69), placental weight (418–1030g) and placental:fetal weight (0.14–0.31). There was no statistically significant change in the rate of nutrient transfer per placenta or per kg fetal weight, with birth weight, birth weight centile, ponderal index, placental weight and placental:fetal weight. There was a weak but significant relationship ( P =0.020, r 2 =9 per cent) between the ratio of glucose to fatty acid transport and birth weight centile, largely due to the high ratio found in the lowest birth weight quartile where the babies are thinnest. This study provides no evidence that placental nutrient transport capacity limits fetal growth across a wide range of birth weights in normal pregnancies. It is proposed that the fetus itself may regulate placental nutrient transport in vivo via the fetal cardiac output and the rate of fetal nutrient utilization.

BACKGROUND Increasing numbers of children are being conceived by assisted reproductive technology (ART). A number of studies have highlighted an altered epigenetic status in gametes from infertile couples and the possibility of an increased risk of imprinting defects and somatic epigenetic changes in ART conceived children, but the results have been heterogeneous. We performed a systematic review of existing studies to compare the incidence of imprinting disorders and levels of DNA methylation in key imprinted genes in children conceived through in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with those in children conceived spontaneously. METHODS A detailed search strategy was used to conduct electronic literature searches (spanning 1978 to 2013) on Medline, EMBASE, the Cochrane Library and Web of Science. Abstracts of relevant conference papers were identified. As randomized trials are not feasible in this context, we included observational (cohort and case–control) studies comparing outcomes in children conceived through ART with those conceived spontaneously, irrespective of the language of publication. The outcome measures were DNA methylation and the incidence of imprinting disorders. RESULTS A total of 351 publications were identified by the initial search. Of these, 26 were excluded as duplicates and 241 were excluded after reviewing the abstracts, then of those remaining 66 were excluded after review of the full text. A total of 18 papers were included in the review. Apart from one case–control study, all were cohort studies. There was a degree of clinical heterogeneity in terms of the study population, type of infertility treatment, and samples obtained from exposed and unexposed children. DNA methylation levels were either presented as categorical data (hypo-, hyper- or normally methylated DNA) or continuous data (i.e. percentage of methylated DNA). The combined odds ratio (95% confidence intervals) of any imprinting disorder in children conceived through ART was 3.67 (1.39, 9.74) in comparison with spontaneously conceived children. Meta-analysis of data from relevant studies revealed that the weighted mean difference (95% confidence intervals) in methylation percent between IVF/ICSI versus spontaneously conceived children were as follows: H19: −0.46(−1.41, 0.49), PEG1-MEST: 0.47 (−2.07, 3.01), GRB10: −0.05 (−0.43, 0.33), IGF2: −0.15 (−1.09, 0.79), SNRPN: −0.55 (−1.55, 0.46), KvDMR/KCNQ10T1: −0.16 (−0.34, 0.02) and PEG3: −0.24 (−1.72, 1.24). CONCLUSIONS There was an increase in imprinting disorders in children conceived though IVF and ICSI but insufficient evidence for an association between ART and methylation in other imprinted genes. Heterogeneity in the types of fertility treatment, the imprinted regions studied, the tissues used and the methods of measurement, reduce our ability to assess the full effect of ART on DNA methylation and imprinting. More controlled studies, using standardized methodologies, in larger, better clinically defined populations are needed.

Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that the genetic etiologies of AD and non-pathological cognitive decline differ.

The purpose of the present study was to estimate whole-body fatty acid and cholesterol synthesis in weight-stable adults and to determine the likely effect on the doubly-labelled water (DLW) method for measuring energy expenditure. Synthesis was measured by2H incorporation over 14 d in six adult males in approximate energy balance following noradrenaline infusion to maximize mobilization of free fatty acid from adipose tissue. The inter-individual variation in synthesis rates was large and in one subject the proportion of free fatty acid synthesized was ten times that of the mean of the rest of the group; the fasting concentration of esterified fatty acid in this subject was five times that of the rest of the group indicating likely violation of the assumptions underlying the calculation of whole-body synthesis. After 14 d of labelling in the other five subjects, 0·9 (SEM 0·3) % OF THE CIRCULATING FREE FATTY ACID, 9·3 (sem 3·0) % of the esterified fatty acid, 14·6 (sem 2·4) % of the free cholesterol and 28·3 (sem 3·7) % of esterified cholesterol had been synthesizedde novo. A high rate of synthesis correlated with a low pre-dose2H abundance both within and between lipid classes suggesting that natural2H abundance variations in some lipid classes may be used to determine their metabolic origin. Whole-body synthetic rates were 8 g/d for fatty acid and 0·3–0·5 g/d for cholesterol. These values correspond to very small errors on DLW-derived estimates of CO2production; -2·5 litres/d for fatty acid and -0·1 to -0·2 litres/d for cholesterol. These results, obtained in subjects typically consuming a diet with a lower fat and cholesterol content that the typical Western diet, suggest that the DLW method is unlikely to be affected by fatty acid and cholesterol synthesis in subjects in energy balance consuming a typical Western diet.

The aim of this study was to determine the effect of fatty acid intake and insulin dependent diabetes on the fatty acid composition of maternal erythrocytes, the placenta and cord. Fatty acid intake (from food frequency questionnaire) and the fatty acid composition of maternal erythrocytes, the placenta and cord from pregnant vegetarians (n = 4) and insulin dependent diabetics (n = 5) was compared with pregnant omnivores (n = 10). There was a significantly lower intake of n-6 long chain polyunsaturated fatty acid (LCPUFA) (-75% P < 0.01) and n-3 LCPUFA (-92% P < 0.01) and increased ratio of n-6/n-3 LCPUFA in the vegetarians (103%; P < 0.001). The concentrations of 22:4 n-6 (+28%; P < 0.05) and 22:5 n-3 (+40%; P < 0.05) were higher in vegetarian erythrocytes. Placental 18:2 n-6 (+26.9%; P < 0.05) 18:3 n-3 (+139%; P < 0.05) and 22:5 n-3 (+24%; P < 0.05) were increased while 20:5 n-3 (-36%; P < 0.05), 22:6 n-3 (-16%; P = 0.059), and the ratios of 20:4 n-6/18:2 n-6 (P < 0.01) and 22:6 n-3/18:3 n-3 were reduced. 22:6 n-6 (-49%; P < 0.05) and total n-3 LCPUFA (-11%; P < 0.01) were reduced in vegetarian cord. For the diabetic mothers, all of the n-6 LCPUFA and n-3 LCPUFA were reduced in the maternal erythrocytes; 22:4 n-6 (-42%; P < 0.05), 22:5 n-6 (-46%; P < 0.05) and 22:6 n-3 (-41%; P < 0.05). For the diabetic placenta and cord the general pattern of n-3 LCPUFA was the same as that in the vegetarians. In the vegetarian mothers, the PUFA profiles in the maternal erythrocytes, placenta and cord are consistent with an elevation in the rate of LCPUFA synthesis in order to make up the relative deficit in LCPUFA intake. However, it may be that the higher level of desaturase activity is not able to overcome the dietary deficit of 22-6 n-3 and 22:6 n-6. Despite the fact that the dietary LCPUFA intake in the pregnant diabetic was comparable with that in the pregnant 'normal' omnivore mothers, the pattern of PUFA in the tissues resembled that of the vegetarian mothers.

The role of the placenta in controlling the supply of fatty acids to the fetus was investigated in term placentae (n = 9) from normal pregnancies. The maternal side was perfused ex vivo for 90 min with a modified Krebs Ringer solution containing a physiological mixture of fatty acids and ratio of fatty acid to human albumin. There was no evidence of chain elongation and desaturation of the essential fatty acids. Relative to the value for oleic acid, the rate of transfer to the fetal circulation was: 1.30 +/- 0.02 (P0.001) for linoleic acid, 1.61 +/- 0.09 (P = 0.002) for alpha-linolenic acid, 0.67 +/- 0.10 (P = 0.033) for arachidonic acid and 2.10 +/- 0.16 (P = 0.003) for docosahexaenoic acid. For tissue accumulation the values were 1.47 +/- 0.39 (P0.001) for linoleic acid, 2.24 +/- 0.37 (P = 0.027) for alpha-linolenic acid, 9.84 +/- 1.03 (P = 0.001) for arachidonic acid, and 3.01 +/- 0.79 (P = 0.064) for docosahexaenoic acid. The order of selectivity for transfer from the maternal to the fetal circulation was docosahexaenoicalpha-linoleniclinoleicoleicarachidonic acid. Such a mechanism would allow the preferential transfer of docosahexaenoic acid and the essential fatty acids to the fetal circulation, thereby protecting the polyunsaturated fatty acid supply to the fetus during a critical period of development.

Free-living energy expenditure was estimated by doubly-labelled water (DLW) and continuous heart-rate (HR) monitoring over nine consecutive days in nine healthy men with sedentary occupations but different levels of leisure-time physical activity. Individual calibrations of the HR-energy expenditure (EE) relationship were obtained for each subject using 30 min average values of HR and EE obtained during 24h whole-body calorimetry with a defined exercise protocol, and additional data points for individual leisure activities measured with an Oxylog portable O2 consumption meter. The HR data were processed to remove spurious values and insert missing data before the calculation of EE from second-order polynomial equations relating EE to HR. After data processing, the HR-derived EE for this group of subjects was on average 0.8 (sem 0.6) MJ/d, or 6.0 (sem 4.2)% higher than that estimated by DLW. The diary-respirometer method, used over the same 9d, gave values which were 1.9 (sem 0.7) MJ/d, or -12.1 (sem 4.0)% lower than the DLW method. The results suggest that HR monitoring can provide a better estimate of 24 h EE of groups than the diary-respirometer method, but show that both methods can introduce errors of 20% or more in individuals.

The present study was designed to investigate the interaction between body weight and energy expenditure in well-nourished individuals. Energy expenditure was determined during a 10 d highly controlled work programme in apparently well-nourished adult male construction workers with a wide range of body weights (mean weight: 63·9 (SD 11·0, range 46·7-80·1) kg, mean BMI: 22·5 (SD 3·8, range 16·7-28·9) kg/m2). Total energy expenditure (mean: 12·68 (SE 0·73) MJ/d or 1·78 (SE 0·07) x BMR) was determined using doubly-labelled water and the energy costs of work activities by Oxylog. The energy expenditure during work (mean: 5·75 (SE 0·29) MJ/day or 3·48 (SE 0·09) x BMR) was estimated from the energy costs of individual tasks and the time spent in those tasks. The energy expenditure during discretionary time (mean: 4·37 (SE 0·58) MJ/d or 1·49 (SE 0·17) x BMR) was calculated by subtracting occupation and sleep expenditure (taken as1 x BMR) from total expenditure. Food intake and discretionary time allocation were recorded by the subjects. The energy expenditure in the programmed work activities (expressed as a multiple of BMR) showed a significant increase (P=0·035) with increasing body weight, suggesting that the assumed constancy of BMR multiples across a wide range of body weights may not be valid. This assertion was supported by theoretical calculations based on empirically derived equations. In order to avoid errors which could be interpreted as metabolic ‘adaptation’ it may be necessary to take account of body weight when using the BMR-multiple approach to estimate energy requirements at low body weights.

The human diet has undergone profound changes over recent generations and this trend is likely to accelerate in the 21st century. Innovations in food technology, new ways of producing and processing foods and the increasing use of artificial vitamins and novel ingredients are changing the human diet in ways that our dietary monitoring systems struggle to keep pace with. There is a growing awareness of the importance of diet, but little understanding of how these changes may affect the health of current and future generations. Epigenetic programming, and specifically the persistence of functional epigenetic states following nutritional exposure, is particularly relevant to the issue of dietary change. Epigenetics is emerging as perhaps the most important mechanism through which diet and nutrition can directly influence the genome and there is now considerable evidence for nutritional epigenetic programming of health and the response to diet itself. A number of nutrients and food components that are changing in the human diet have been shown to produce epigenetic states that are stable across different timescales. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and the response to diet.

The main nutritional role of the placenta is to provide the correct mix of nutrients in sufficient quantities to support fetal growth and development throughout pregnancy while coping with wide variations in maternal nutrient intake between pregnancies and temporal variations within a pregnancy. The placenta represents a nutritional ‘bottleneck’ where competition for nutrient transporters and metabolic selectivity, acting in concert with maternal adaptations, allows the placenta to regulate the nutrient mix within the fetal circulation. The fetus itself also plays an active role in regulating key aspects of placental transport in order to meet its own nutrient requirements.