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- W2894326141 abstract "In 1942, Conrad H Waddington introduced the term ‘epigenetics’, to describe a biological process that takes place between the genotype and phenotype.1 Epigenetics was subsequently defined as ‘the study of mitotically and meiotically heritable changes in gene function that cannot be explained by changes in DNA sequences’.2 It is a gene-marking and gene-regulatory system that is essential for normal mammalian development. Examples of epigenetic marks include DNA methylation3 and covalent modifications that are positioned on the histone proteins, the ‘histone code’, which act to regulate chromatin function.4 Of importance to the field of reproductive medicine, epigenetic marks are extensively reprogrammed during gametogenesis and preimplantation embryonic development. These epigenetic modifications, in addition to RNA-based epigenetic mechanisms,5 are important in regulating gene expression.6 The appropriate regulation of epigenetic information is critical to normal development, since the disruption of epigenetic mechanisms can cause disease.7-11 The natural periods during which developmental epigenetic reprogramming in gametes and preimplantation development occur coincide closely with the time during human assisted reproduction that the gametes and embryos are being handled in an in vitro environment. The best understood epigenetic reprogramming cycle is that of DNA methylation. The lifecycle of this epigenetic mark includes several key stages including: the erasure of epigenetic marks from primordial germ cells; the establishment of a new set of marks during gametogenesis; genome-wide erasure of methylation during the preimplantation stages; and de novo establishment of marks during development and differentiation from around the blastocyst stage (that is day 5 of embryo development) onwards.12, 13 Newly-identified processes that act to erase DNA methylation from primordial germ cells and during preimplantation development have been detected.14, 15 Currently, it is not possible to assess the epigenetic status of the human preimplantation embryo during routine assisted reproductive technology (ART). It is not at this time, therefore, possible to deduce: This review will summarise current viewpoints on our understanding of epigenetics and the relevance of these findings to reproductive medicine. Genomic imprinting is a system of gene expression used in mammals, plants and insects that is controlled by epigenetic information16 and is limited to a restricted number of genes.17 It can be defined as the exclusive or predominant expression of one allele of a gene (from either the maternal or paternal allele, depending on the gene in question). For example, the insulin-like growth factor II gene is an imprinted gene expressed from the paternal allele, while the H19 gene is an imprinted gene expressed from the maternal allele. This monoallelic expression is regulated by allele-specific epigenetic marks, such as DNA methylation, which are established in the germline and, importantly, are actively maintained during preimplantation development to allow continued marking and appropriate monoallelic expression of the correct parental allele of the imprinted gene. Imprinted genes are particularly important in the regulation of energy balance between the mother and the developing fetus via the placenta,18, 19 and current hypotheses suggest that genomic imprinting may allow the exertion of parental epigenetic influences on the growth and development of the conceptus.20, 21 Correct imprinted gene transcript dosage is critical for early development.22 Over 200 imprinted genes have been described to date in humans, with many imprinted genes locating to clusters on the chromosomes.23, 24 In humans there are a number of congenital disorders, termed imprinting disorders (IDs), caused by the disruption of imprinted genes, including Beckwith-Wiedemann syndrome (BWS), Silver-Russell syndrome (SRS), and Angelman syndrome (AS).25 Of these, BWS and SRS appear to be associated with assisted reproduction.26-28 A systematic review and meta-analysis of the literature has revealed that the risk of IDs is higher in children conceived through assisted reproduction (in vitro fertilisation [IVF] or intracytoplasmic sperm injection [ICSI]) than in those conceived naturally.29 Summarising data from eight epidemiologic studies of BWS and ART, Vermeiden and Bernardus30 reported a significant positive association between IVF/ICSI treatment and BWS, and described a relative risk of 5.2 (95% CI 1.6–7.4), indicating that one BWS child will be born for every 2700 IVF/ICSI births when using a population prevalence in the general population of 1:13 700. The same report concluded that there probably is a significant positive association between the incidences of SRS and IVF/ICSI treatment, but noted that the number of published cases is small (13 SRS children born after ART). It is important, therefore, to note that while cases of IDs are rare, it is necessary to understand how ART causes epigenetic disruption, in case these outcomes are sentinel indicators of more widespread epigenetic disruption, which may include non-imprinted loci. In addition to experimental data from other mammals, there is evidence from human studies that a number of assisted reproduction procedures, including superovulation, micromanipulation, in vitro maturation of oocytes and embryo culture, can cause epigenetic disruption.31-33 Unfortunately, assisted reproduction procedures are performed at a time when dynamic, essential epigenetic reprogramming events are occurring in the gametes and embryos, yet the extent of these epigenetic changes and the relevance to human health and disease in assisted reproduction cohorts is only just beginning to be understood. It is important, therefore, that the use of assisted reproduction should be closely monitored.34 Two assisted reproduction procedures will be discussed in detail here as examples of how these may lead to epigenetic disturbance. A large number of publications have described the effects of in vitro culture (IVC) on gene expression in preimplantation embryos from several mammalian species.31, 35, 36 The expression and/or methylation of a number of imprinted genes are disrupted by IVC in some, but not all, types of culture media.37-41 Arguably the most comprehensive assessment to date was reported by Schwarzer et al.,42 who demonstrated that culture media can induce a wide range of cellular, developmental and metabolic changes in mouse preimplantation embryos, including effects on metabolic pathways, a conclusion reinforced by Gad et al.43 Very few studies have investigated the effects of culture media in human preimplantation embryos. Kleijkers et al.44 reported that genes from several pathways were differentially expressed in the two media tested (G5 medium and human tubal fluid medium). In a more recent study by Mantikou et al.45 174 genes were differentially expressed in human embryos cultured using these same two media. Given the current interest in developing embryo culture media that contain growth factors, it is also worth noting that Kimber et al.46 showed that single growth factors added to human embryos in culture caused unexpected changes in gene expression profiles. In contrast, a histological study in mice reported that the appearance of the placentas or fetuses derived from embryos cultured in different media did not differ, however, this study did not involve molecular analysis.47 A further example of the detrimental effects of IVC is illustrated by large offspring syndrome (LOS), which may be observed after IVC in ruminants and results in the fetus growing large in the uterus, bringing risks to the mother as well as the offspring.48 In a comprehensive genetic analysis using RNA sequencing, LOS was revealed to involve a multi-locus loss of imprinting syndrome.49 These studies highlight that in some circumstances, IVC has the potential for inflicting genome-wide changes in gene expression/methylation that can have developmental consequences. Birthweight is an important metric as it is a useful, routinely collected surrogate for fetal growth and, along with early postnatal growth, a strong predictor of the long-term risk of cardiometabolic disease.50, 51 In a comparative study of two commercially available media used for IVC of fresh embryos, Dumoulin et al.52 reported a significant difference in birthweight (3453 ± 53 g [sample error of the mean] versus 3208 ± 61 g, P = 0.003) and in birthweight adjusted for gestational age and gender. Similar findings were reported in a subsequent study from the same group53 performed in a larger cohort. Furthermore, differences in postnatal weight were observed during the first 2 years of life.54 In another study, no significant differences in mean birthweight or mean birth length were reported comparing three other types of embryo culture media.55 Further studies56-58 using a range of media also failed to reveal significant differences in birthweight. Other culture conditions that might affect birthweight are the age of the media,59 the length of the culture period (relevant to the extended culture periods used in blastocyst culture versus cleavage-stage transfer),60 and the protein source used in the media.61 These studies were summarised by Zandstra et al.,50 who concluded that of 11 media comparisons published, six showed differences in birthweight while five did not. The list of culture conditions presented is not necessarily complete and it is possible that other factors may be identified in the future. A working party of the European Society for Human Reproduction and Embryology has called for national ART registries to track culture media used, to allow the long term assessment of health risk, and encourage full disclosure of media composition by commercial manufacturers.62 From this report, a number of recommendations were made including: The influence of media on pregnancy and perinatal outcome after IVF has also been considered in a randomised control trial, published in 2016.63 This study compared outcomes after embryo culture in either G5 or human tubal fluid media and reported that birthweight was significantly lower in the G5 group while the clinical pregnancy rate was significantly higher. Although the findings of this study were considered controversial by some sectors of industry, they were recently corroborated by an independent statistical analysis.64 Data from animal and human studies indicate that the process of ovarian stimulation may induce epigenetic errors in the oocyte, embryo and placenta. Controlled ovarian hyperstimulation (COH)/superovulation overrides the progressive, oocyte growth-dependent process of epigenetic maturation and imprint establishment,65, 66 or may lead to the recruitment of poor quality oocytes that would not normally be selected to ovulate.67, 68 COH in humans is associated with epigenetic changes at a small number of tested loci69, 70 and was reported as the only common factor in the medical records of women who gave birth to children with BWS after ART.71 Mouse studies have identified transgenerational effects of superovulation,72 with epigenetic changes persisting in the sperm of the second generation offspring of superovulated mothers. Superovulation has also been reported to cause perturbed genomic imprinting of maternally- and paternally-expressed genes in the embryo and placenta,68, 73 and is therefore likely to disrupt key oocyte/early embryo-specific factors important for imprint maintenance during preimplantation development.74-76 Epigenetic errors have been reported to be inherent in arrested human embryos.77 Several studies have indicated that imprinted genes such as SNRPN, H19, PEG1/MEST, KCNQ1OT1 and imprinted gene regulatory regions in some human preimplantation embryos may be susceptible to abnormal DNA methylation patterns or gene expression patterns.36, 78-80 Such studies include analysis of KvDMR1,a the DMR that is aberrantly methylated in ART-related BWS in humans, and is hypomethylated in LOS following assisted reproduction in bovine embryos.81-85 However, the merits of attempting to measure ‘epigenetic health’ with methylation data obtained from such a restricted number of loci is currently limited, since there is insufficient knowledge of developmental epigenetic processes in humans to demonstrate conclusively whether any particular epigenetic defect detected in the preimplantation embryo will cause disease in the infant at birth or might be manifest later in development. In addition to effects induced by ART, it is important to consider cases of infertility in which gametogenesis itself is susceptible to epigenetic defects. Perturbed epigenetic signatures in sperm are observed in cases of male infertility,86, 87 and epigenetic screening of sperm may be of potential use clinically.88-90 There may be equivalent epigenetic defects in the female germline associated with female infertility. Kobayashi et al.91 indicated that in some cases epigenetic errors may be inherited from the sperm, but other studies suggest that epigenetic defects are due to the procedure itself rather than defects in the gametes.79, 80, 92 It remains possible that pre-existing gametic epigenetic defects could be exacerbated by suboptimal conditions in assisted reproduction. Other features of couples presenting for ART must also be considered, for example, advanced age, diet, body composition, environmental exposures and genetic/epigenetic variation, which have all been shown to affect epigenetic programming in the mammalian germline.86, 93-97 The epigenetic profiles of ART cohorts appear to differ from those naturally conceived, as summarised by Batcheller et al.98 However, studies have been limited by the type of assay used, its coverage of the genome and the type of cell used for analysis. In more recent work, quantitative assessment of methylation indicated that use of ICSI was associated with a higher level of SNRPN methylation.99 In another study, Melamed et al.100 used a methylation array, which allows wider sampling of the genome, and revealed that hypomethylation was observed in the assisted reproduction group. It was concluded that ART may be associated with significantly higher variation in DNA methylation compared with natural conception, in agreement with other studies.27 Several studies have indicated that ARTs are associated with fetal growth restriction, prematurity, low birthweight for gestational age, and slightly increased risk of cardiovascular malformations and other defects.101, 102 Long-term follow-up studies (reviewed in Hart and Norman103) have suggested a potential increase in the incidence of elevated blood pressure and fasting glucose, and increased total body fat in IVF offspring. Systemic and pulmonary vascular dysfunction104 and right ventricular dysfunction105 have been observed in children and adolescents conceived through ART. Assisted reproduction may also lead to cardiac and vascular remodelling that persists in human fetal and postnatal development.106 Cardiovascular and metabolic effects are also seen in mouse studies where there is evidence for an epigenetic origin for these problems.107 Thus, in mice conceived by IVF epigenetic changes were observed at imprinted genes, alongside methylation and expression of the endothelial nitric oxide synthase gene and arterial function in the aorta. Other studies support this growing body of evidence that there may be increased risks for metabolic and cardiovascular diseases following ART.108-113 It is possible that these outcomes are a result of the alteration/adaptation of metabolic pathways in mammalian embryos exposed to suboptimal culture media and/or environments.42-44 Indeed, many enzymes involved in epigenetic gene regulation in eukaryotic cells make use of co-substrates and co-factors generated by cellular metabolism, thereby providing a direct link between culture environment and gene regulation.114 Examples include cellular fluctuations in acetyl coenzyme A and histone acetylation, nicotinamide adenine dinucleotide and sirtuin deacetylase activity, and S-adenosylmethionine and histone/DNA methylation. Of these metabolic intermediaries, disturbances to S-adenosylmethionine-mediated epigenetic regulation during embryonic development has been the most comprehensively studied, influenced as it is by inputs into 1-carbon metabolic pathways.115 These inputs include a diverse range of B vitamins (e.g. B12, folate [B9] and B6) and elements such as sulphur, zinc and cobalt. These in turn are influenced by lifestyle factors including obesity, cigarette smoking, alcohol and caffeine consumption,116 which can lead to epigenetic dysregulation of gene expression in fetal tissues during early pregnancy.117 The accumulating evidence indicates that a more holistic approach is required when offering guidance to couples undergoing fertility treatment that extends to dietary advice and lifestyle choices, although clearly further research is required. Strategies that avoid excessive use of ART should be considered. Assisted reproduction pregnancies have been associated with larger placentas and higher placental weight/birthweight ratios118 in addition to modified imprinted gene expression and/or methylation in the placenta119 and cord blood.120 Such findings are likely to be important since imprinted genes are highly expressed and play a pivotal role in placental function.121 In mouse experiments, ART can lead to multiple detrimental effects in the placenta39, 122-125 which collectively provide molecular evidence that assisted reproduction can adversely affect placental function, with the potential to influence long term health.126 This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: Dr J Huntriss, Discovery and Translational Science Department (DTSD), Leeds Institute of Cardiovascular and Metabolic Medicine; Professor AH Balen FRCOG, Leeds; Professor KD Sinclair, School of Biosciences, University of Nottingham; Professor DR Brison, Department of Reproductive Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre; and Professor HM Picton, DTSD, Leeds Institute of Cardiovascular and Metabolic Medicine and peer reviewed by: British Fertility Society; Dr A Drake MBBS PhD FRCPCH, Centre for Cardiovascular Science, The University of Edinburgh; Mr DI Fraser FRCOG, Norwich; and RCOG Women's Network. The Scientific Advisory Committee lead reviewer was: Professor H Leese FRCOG, Hull. The chair of the Scientific Advisory Committee was: Dr S Ghaem-Maghami MRCOG, London. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this Scientific Impact Paper is available from: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/sip57/. The final version is the responsibility of the Scientific Advisory Committee of the RCOG. The paper will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication. The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient's case notes at the time the relevant decision is taken." @default.
- W2894326141 created "2018-10-05" @default.
- W2894326141 creator A5003101926 @default.
- W2894326141 creator A5006353998 @default.
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- W2894326141 date "2018-09-24" @default.
- W2894326141 modified "2023-09-30" @default.
- W2894326141 title "Epigenetics and Reproductive Medicine" @default.
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