Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants

Estill, Molly; Bolnick, Jay M.; Waterland, Robert A.; Bolnick, Alan; Diamond, Michael P.; Krawetz, Stephen A.

doi:10.1016/j.fertnstert.2016.05.006

Cited by 86 publications

(78 citation statements)

References 64 publications

(91 reference statements)

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“…A particular strength of this study is that the embryos in both IVF groups were transferred into physiologic hormonal environments, thus minimizing the confounding effects of superovulation on the endometrium. Several other studies have reported similar patterns in other genes related to growth, with frozen embryos yielding epigenetic patterns and gene expression more similar to natural conception (Estill et al, ; Ghosh, Coutifaris, Sapienza, & Mainigi, ). This suggests a potential mechanism of vitrification resulting in reversal of the epigenetic effects of superovulation on the oocyte, with consequentially larger babies.…”

Section: Proposed Mechanismsmentioning

confidence: 61%

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization

Heertum

Weinerman

2018

Birth Defects Research

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In vitro fertilization (IVF) and embryo cryopreservation have become increasingly common in recent years. As utilization increases, it is important to understand the clinical effects these technologies have on offspring, as well as the mechanisms behind these effects. Many epidemiologic studies have observed that pregnancies following IVF are more likely to be affected by obstetric complications such as pre‐eclampsia, preterm birth, and small for gestational age neonates compared with naturally conceived pregnancies. There has been a great deal of research emerging suggesting that these differences are related to the supraphysiologic hormonal environment that results from ovarian superovulation. While pregnancies resulting from frozen embryo transfer are less likely to experience these complications, babies born after frozen transfer are more likely to be large for gestational age. Epigenetic studies point toward differential methylation of genes critical for growth that may be responsible for the increased incidence of larger neonates following transfer of vitrified embryos. Although it does appear that perinatal outcomes are improved by transferring frozen embryos instead of fresh, it would be premature at this time to recommend universal freeze‐all protocols in all patients. This article, as part of the “IVF Reviews” special issue of this journal, aims to expound on the issues outlined above.

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Section: Proposed Mechanismsmentioning

confidence: 61%

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization

Heertum

Weinerman

2018

Birth Defects Research

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“…It has been reported that global genomic methylation in vitrification groups is lower in mouse MII oocytes, two to eight cell embryos and blastocysts than in controls (Chen, Shi et al, ; Cheng et al, ; Liang et al, ; Yao et al, ). However, the methylation profiles of infants obtained through ICSI‐frozen (FET) and intrauterine insemination (IUI) methods are strikingly similar, and this finding was similar to our results (Estill et al, ). Thus, we infer that the methylation changes observed in the VET group and IVC group might be important for ART clinics.…”

Section: Discussionmentioning

confidence: 99%

Changes in DNA methylation and imprinting disorders in E9.5 mouse fetuses and placentas derived from vitrified eight‐cell embryos

Wen

et al. 2019

Molecular Reproduction Devel

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Vitrification is increasingly used in assisted reproductive technology (ART) laboratories worldwide, and potential vitrification‐induced risks require further exploration. The effect of vitrification on changes in DNA methylation and imprinting disorders was investigated in E9.5 mouse fetuses and placentas. Fetus and placental tissues were collected from the natural mating (nautural conception [NC]) group, in vitro culture (IVC) group and vitrified embryo transfer (VET) group. The fetal crown‐rump length at E9.5 in both the IVC (0.210 ± 0.059 mm) and VET (0.205 ± 0.048 mm) groups was significantly reduced compared with the NC group (0.288 ± 0.083 mm). The global methylation levels of fetuses were decreased in the IVC group compared with the NC group and it was increased after vitrification compared with IVC (p < 0.05), similar to what was observed in the NC group (p > 0.05). The changes could be attributed to the disorders of DNA methyltransferases and ten‐eleven translocations. In the IVC and VET fetuses, a majority of maternally expressed genes were upregulated, which repressed fetal growth. Furthermore, vitrification led to a change in the methylation level of KvDMR1, which resulted in the disturbance of gene imprinting. According to our results, vitrification could contribute to increased methylation compared with IVC and contributes to a gene imprinting disorder rather than recovery. Despite the routine use of embryo vitrification in clinical settings, the effect that this procedure may have on genomic imprinting deserves much greater attention.

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“…They addressed several caveats of the IVF process including epigenetic erasure and reprogramming. However, in light of more recent evidence that IVF alters DNA methylation [26,27] and the expression of microRNAs in the fetal brain that regulate neuronal migration, differentiation and development [28], one should be cautious in interpreting IVF experiments with respect to epigenetic mechanisms mediating transgenerationally transmitted effects of paternal stress [see 22 for further discussion of this issue].…”

Section: Paternal Stress Influences Male Offspring Anxiety and Depresmentioning

confidence: 99%

Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes

Pang

Short

Bredy

et al. 2017

Current Opinion in Behavioral Sciences

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In recent years, it has become evident that pre-conceptual exposure of males to various environmental factors induces epigenetic changes in sperm, which can mediate the transmission of acquired traits in their offspring. The most thoroughly examined paternal exposures involve stress and elevated corticosterone, which have been shown to modulate offspring phenotypes in a manner that is relevant to predisposition to brain disorders, and psychiatric illness in particular. Recent seminal studies have demonstrated that key epigenetic information transmitted via the paternal germline involves small non-coding (snc) RNA transcripts such as microRNAs. Following fertilisation, these sncRNAs appear to regulate development so as to modify the phenotype of the offspring. Understanding the mechanisms involved in such transgenerational effects may facilitate future screening of human sperm for ‘epigenetic health’ and the tailoring of therapeutic interventions according to genetic and epigenetic contributions to illness.

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Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants

Cited by 86 publications

References 64 publications

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization

Neonatal outcomes following fresh as compared to frozen/thawed embryo transfer in in vitro fertilization

Changes in DNA methylation and imprinting disorders in E9.5 mouse fetuses and placentas derived from vitrified eight‐cell embryos

Transgenerational paternal transmission of acquired traits: stress-induced modification of the sperm regulatory transcriptome and offspring phenotypes

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