Search

With a rising worldwide incidence of obesity, particularly in the young, bariatric surgery offers an effective method of meaningful and sustained weight loss. At present, most bariatric procedures are carried out in women and increasingly in younger age groups. In line with the fertility benefits associated with weight loss, pregnancy after bariatric surgery is now a very common scenario. Although there is limited evidence to support optimal care in this group, most women appear to have good pregnancy outcomes, with reduced rates of preeclampsia and gestational diabetes (GDM). However, rates of stillbirth and small-for gestational-age (SGA) babies are increased, suggesting that screening and supplementation of micronutrients is likely to be very important in this cohort. The risks and benefits bariatric surgery may pose to pregnancy outcomes, both maternal and fetal, are largely dependent upon the degree of weight loss, weight stability upon entering pregnancy, surgical complications and the time interval between bariatric surgery and pregnancy. Ideally, preconception care would be more widely available, helping to assess and address micronutrient deficiencies and support preparation for pregnancy., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Claire L Meek reports a relationship with NIHR Leicester BRC that includes: funding grants. Claire L Meek reports a relationship with European Foundation for the Study of Diabetes that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

A universal response to cellular stress is the expression of transformation-related protein 53 (TRP53). This transcription factor reduces cell proliferation and/or survival and is classed as a tumour suppressor protein. Several stresses (including culture) cause increased TRP53 expression in blastocysts and their reduced long-term developmental potential. This study shows that culture from the zygote stage (but not the 2-cell stage) reduced the development of C57BL6 inbred (but not hybrid) strain mouse embryos. Reduced viability was TRP53 dependent, being partially reversed by a TRP53 inhibitor (Pifithrin-alpha). However, the presence of culture did not cause an increase in Trp53 mRNA levels (levels were reduced following culture, P < 0.001). Transformed mouse 3T3 cell double minute 2 (MDM2) causes the ubiquitination and degradation of TRP53. MDM2 activation is accompanied by phosphorylation of Ser-166, and this is commonly catalyzed by the phosphatidylinositol-3 kinase and RAC-alpha serine/threonine-protein kinase (AKT) signaling pathway. Paf is an autocrine embryotrophin that activates the phosphatidylinositol-3 kinase/AKT pathway. High levels of TRP53 expression occurred following the culture of zygotes lacking the Paf receptor (Ptafr(-/-)) and following inhibition of phosphatidylinositol-3 kinase or AKT. Inhibition of MDM2 caused a Trp53-dependent reduction in zygote development. Inbred strain embryos cultured from the zygote stage expressed less phosphorylated MDM2 than similar embryos collected from the uterus. The addition of Paf to the media caused increased phosphorylation of MDM2, and this was blocked by inhibitors of phosphatidylinositol-3 kinase and AKT. The study identifies trophic ligand signaling via the activation of phosphatidylinositol-3 kinase and AKT as a mechanism resulting in the activation of MDM2.

A universal response to cellular stress is the expression of transformation-related protein 53 (TRP53). This transcription factor reduces cell proliferation and/or survival and is classed as a tumour suppressor protein. Several stresses (including culture) cause increased TRP53 expression in blastocysts and their reduced long-term developmental potential. This study shows that culture from the zygote stage (but not the 2-cell stage) reduced the development of C57BL6 inbred (but not hybrid) strain mouse embryos. Reduced viability was TRP53 dependent, being partially reversed by a TRP53 inhibitor (Pifithrin-alpha). However, the presence of culture did not cause an increase in Trp53 mRNA levels (levels were reduced following culture, P < 0.001). Transformed mouse 3T3 cell double minute 2 (MDM2) causes the ubiquitination and degradation of TRP53. MDM2 activation is accompanied by phosphorylation of Ser-166, and this is commonly catalyzed by the phosphatidylinositol-3 kinase and RAC-alpha serine/threonine-protein kinase (AKT) signaling pathway. Paf is an autocrine embryotrophin that activates the phosphatidylinositol-3 kinase/AKT pathway. High levels of TRP53 expression occurred following the culture of zygotes lacking the Paf receptor (Ptafr(-/-)) and following inhibition of phosphatidylinositol-3 kinase or AKT. Inhibition of MDM2 caused a Trp53-dependent reduction in zygote development. Inbred strain embryos cultured from the zygote stage expressed less phosphorylated MDM2 than similar embryos collected from the uterus. The addition of Paf to the media caused increased phosphorylation of MDM2, and this was blocked by inhibitors of phosphatidylinositol-3 kinase and AKT. The study identifies trophic ligand signaling via the activation of phosphatidylinositol-3 kinase and AKT as a mechanism resulting in the activation of MDM2.

Restricting the growth of the embryo can cause adverse whole-of-life changes in an organism's homeostasis. Such adverse long-term consequences may occur even when growth restriction occurs only during the preimplantation period. The molecular basis for these long-term effects has not been defined, although an epigenetic mechanism is suspected. Some loci seem to be more sensitive to epigenetic perturbation than others, and the agouti viable yellow allele (A(vy)) is the best studied example of this. It has active (hypomethylated) and inactive (hypermethylated) epialleles. This study used the A(vy) model to show that growth restriction of preimplantation embryos, as provided by culture of zygotes, induced persistent epigenetic changes that resulted in altered postnatal phenotype. C57BL/6 A(vy)/a males were mated to ovulation-induced FVB/N females, and then either zygotes were collected and cultured for 96 h and the resulting blastocysts were transferred to pseudopregnant recipient females, blastocysts were collected from females and transferred without embryo culture, or pregnancy was allowed to proceed after mating without intervention. Culture was in a commercial human in vitro fertilization media. The proportion of pups expressing the active (hypomethylated) epiallele and yellow coat was significantly higher following zygote culture compared to embryos that were transferred without culture (P = 0.014) or natural matings (P < 0.001). There was no difference in expression of the active epiallele in pups resulting from embryo transfer (without culture) compared to natural matings. These results show for the first time that the preimplantation embryo's growth environment can affect the postnatal expression of a defined epigenetically sensitive allele.

Background and Aims: Species' 2C-values (mass of DNA in G(1) phase 2n nuclei) vary by at least four orders of magnitude among seed plants. The 2C-value has been shown to be co-ordinated with a number of other species traits, and with environmental variables. A prediction that species 2C-values are negatively related to leaf life span (LL) and leaf mass per area (LMA) is tested. These leaf traits are components of a major dimension of ecological variation among plant species., Methods: Flow cytometry was used to measure the 2C-values for 41 Australian seed plant species, 40 of which were new to the literature. Where possible, LL and LMA data from the global literature were combined with 2C-values from our data set and online C-value databases., Key Results: Across all species, weak positive relationships were found between 2C-values and both LL and LMA; however, these did not reflect the relationships within either angiosperms or gymnosperms. Across 59 angiosperm species, there were weak negative relationships between 2C-values and both LL (r2 = 0.13, P = 0.005) and LMA (r2 = 0.15, P = 0.002). These relationships were the result of shifts to longer LL and greater LMA in woody compared with herbaceous growth forms, with no relationships present within growth forms. It was not possible to explain a positive relationship between 2C-values and LMA (r2 = 0.30, P = 0.024) across 17 gymnosperm species. The 2C-value was not related to LL or LMA either across species within orders (except for LMA among Pinales), or as radiation divergences in a model phylogeny., Conclusions: Gymnosperms appear to vary along a spectrum different from angiosperms. Among angiosperms, weak negative cross-species relationships were associated with growth form differences, and traced to a few divergences deep in the model phylogeny. These results suggest that among angiosperms, nuclear DNA content and leaf strategy are unrelated.

DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C --> T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. The Aid and Apobec1 genes are located in a cluster of pluripotency genes including Nanog and Stella and are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.

Phenotypic variation that cannot be explained by genetic or environmental heterogeneity has intrigued geneticists for decades. The molecular basis of this phenomenon, however, is largely a mystery. Axin-fused (Axin(Fu)), first identified in 1937, is a classic example of a mammalian allele displaying extremely variable expression states. Here we demonstrate that the presence or absence of its characteristic phenotype, a kinked tail, correlates with differential DNA methylation at a retrotransposon within Axin(Fu) and identify mutant transcripts arising adjacent to the retrotransposon LTR that are likely to be causative of the phenotype. Furthermore, the epigenetic state at Axin(Fu) can be inherited transgenerationally after both maternal and paternal transmission. This is in contrast to epigenetic inheritance at the murine agouti-viable yellow (A(vy)) allele, which occurs through the female only. Unlike the egg, the sperm contributes very little (if any) cytoplasm to the zygote, and therefore paternal inheritance at Axin(Fu) argues against the possibility that the effects are due to cytoplasmic or metabolic influences. Consistent with the idea of transgenerational inheritance of epigenetic marks, we find that the methylation state of Axin(Fu) in mature sperm reflects the methylation state of the allele in the somatic tissue of the animal, suggesting that it does not undergo epigenetic reprogramming during gametogenesis. Finally, we show that epigenetic inheritance is influenced by strain background. These findings enable us to propose a model for transgenerational epigenetic inheritance in mammals.

It is well recognized that there is a surprising degree of phenotypic variation among genetically identical individuals, even when the environmental influences, in the strict sense of the word, are identical. Genetic textbooks acknowledge this fact and use different terms, such as 'intangible variation' or 'developmental noise', to describe it. We believe that this intangible variation results from the stochastic establishment of epigenetic modifications to the DNA nucleotide sequence. These modifications, which may involve cytosine methylation and chromatin remodelling, result in alterations in gene expression which, in turn, affects the phenotype of the organism. Recent evidence, from our work and that of others in mice, suggests that these epigenetic modifications, which in the past were thought to be cleared and reset on passage through the germline, may sometimes be inherited to the next generation. This is termed epigenetic inheritance, and while this process has been well recognized in plants, the recent findings in mice force us to consider the implications of this type of inheritance in mammals. At this stage we do not know how extensive this phenomenon is in humans, but it may well turn out to be the explanation for some diseases which appear to be sporadic or show only weak genetic linkage.