The fetus has an absolute requirement for the n-3/n-6 fatty acids and docosahexaenoic acid (22:6 n-3; DHA) in particular is essential for the development of the brain and retina. Most of the fat ...deposition in the fetus occurs in the last 10 weeks of pregnancy. The likely rate of DHA utilisation during late pregnancy cannot be met from dietary sources alone in a significant proportion of mothers. De novo synthesis makes up some of the shortfall but the available evidence suggests that the maternal adipose tissue makes a significant contribution to placental transport to the fetus. The placenta plays a crucial role in mobilising the maternal adipose tissue and actively concentrating and channelling the important n-3/n-6 fatty acids to the fetus via multiple mechanisms including selective uptake by the syncytiotrophoblast, intracellular metabolic channelling, and selective export to the fetal circulation. These mechanisms protect the fetus against low long-chain polyunsaturated fatty acid (LCPUFA) intakes in the last trimester of pregnancy and have the effect of reducing the maternal dietary requirement for preformed DHA at this time. As a result of these adaptations, small changes in the composition of the habitual maternal diet before pregnancy are likely to be more effective in improving LCPUFA delivery to the fetus than large dietary changes in late pregnancy. There is little evidence that DHA intake/status in the second half of pregnancy affects visual and cognitive function in the offspring, but more studies are needed, particularly in children born to vegetarian and vegan and mothers who may have very low intakes of DHA.
BACKGROUND: Little is known of fatty acid metabolism in human embryos. This information would be useful in developing metabolic tests of embryo quality and improving embryo culture media. METHODS: ...The fatty acid composition of human embryos and their ability to accumulate 13C labelled fatty acids was assessed in relation to the stage of development using gas-chromatography and combustion-isotope-ratio-mass spectrometry. RESULTS: Compared with embryos which did not develop beyond the 4-cell stage, those that did had significantly higher concentrations of the unsaturates, linoleic (12% versus 3%; P = 0.02) and oleic (14% versus 7%; P = 0.02), and a lower concentration of total saturates (62% versus 77%; P = 0.04). There was uptake of both 13C linoleic and palmitic, but the developmental pattern was different for each fatty acid. The net accumulation in pmol/embryo/24h for palmitic was 1 at the 2-cell to <8-cell stage, 4 at the 8-cell–morula stage and negligible at the blastocyst stage. For linoleic, there was little net accumulation at the 2-cell to <8-cell stage, 8 (8-cell–morula stage) and 17 pmol/embryo/24h (blastocyst stage). CONCLUSION: Preimplantation human embryos actively take up individual fatty acids at different rates at different stages of development. The high unsaturated concentration at the later stages of development may be explained by preferential uptake of linoleic acid.
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.
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.
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).
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.
Leptin is expressed in the placenta and in certain fetal tissues; however, little is known with regard to the function of this hormone in these tissues. To date, most evidence suggests that placental ...and/or fetal leptin acts as a fetal growth factor, but this is far from clear. Leptin may also have physiological effects on the placenta, including angiogenesis, growth and immunomodulation. The effects of placental leptin, if any, on the mother may contribute to endocrine-mediated alterations in energy balance, such as the mobilization of maternal fat, which occurs during the second half of pregnancy. In this review we will address these and other issues related to the expression of both placental and fetal leptin.
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.
GWAS‐based pathway analysis differentiates between fluid and crystallized intelligence (
gF and
gC).
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 andn -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 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 (
P<0.001) for linoleic acid, 1.61 ± 0.09 (
P=0.002) for α-linolenic acid, 0.67 ± 0.10 (
P=0.033) for arachidonic acid and 2.I0 ± 0.16 (
P=0.003) for docosahexaenoic acid. For tissue accumulation the values were 1.47 ± 0.39 (
P<0.001) for linoleic acid, 2.24 ± 0.37 (
P=0.027) for α-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 docosahexaenoic>α-linolenic>linoleic>oleic>arachidonic 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.
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.
TRIAL REGISTRATION NUMBER
Not applicable.
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