Comparison of Genome-Wide and Gene-Specific DNA Methylation between Pregnancies Conceived Naturally Versus ART (Assisted Reproductive Technologies)

The number of children born since the origin of Assisted Reproductive Technologies (ART) exceeds 5 million. The majority seem healthy, but a higher frequency of defects has been reported among ART-conceived infants, suggesting an epigenetic cost. We report the first whole-genome DNA methylation datasets from single pig blastocysts showing differences between in vivo and in vitro produced embryos. Blastocysts were produced in vitro either without (C-IVF) or in the presence of natural reproductive fluids (Natur-IVF). Natur-IVF embryos were of higher quality than C-IVF in terms of cell number and hatching ability. RNA-Seq and DNA methylation analyses showed that Natur-IVF embryos have expression and methylation patterns closer to in vivo blastocysts. Genes involved in reprogramming, imprinting and development were affected by culture, with fewer aberrations in Natur-IVF embryos. Methylation analysis detected methylated changes in C-IVF, but not in Natur-IVF, at genes whose methylation could be critical, such as IGF2R and NNAT.

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Epigenetic imprinting during assisted reproductive technologies: The effect of temporal and cumulative fluctuations in methionine cycling on the DNA methylation state

Molecular Reproduction and Development ◽

10.1002/mrd.22605 ◽

2016 ◽

Vol 83 (2) ◽

pp. 94-107 ◽

Cited By ~ 7

Author(s):

Lianne Hoeijmakers ◽

Hermannus Kempe ◽

Pernette J. Verschure

Keyword(s):

Dna Methylation ◽

Assisted Reproductive Technologies ◽

Reproductive Technologies ◽

Methylation State

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Epigenetic Effects of Assisted Reproductive Technology in Human Offspring

10.1101/816157 ◽

2019 ◽

Author(s):

Wei Chen ◽

Yong Peng ◽

Xinyi Ma ◽

Siming Kong ◽

Shuangyan Tang ◽

...

Keyword(s):

Embryo Transfer ◽

Assisted Reproductive Technologies ◽

Adult Life ◽

Reproductive Technologies ◽

Fresh Embryo Transfer ◽

Vitro Fertilization ◽

Nuclear Families ◽

Genome Wide ◽

Parental Background

AbstractThe births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the potential for elevated risks of ART-related disorders persists in adult life, and the underlying epigenetic mechanisms are largely uncharacterized. Here, we recruited 100 nuclear families and profiled the DNA methylomes, genome-wide histone modifications and transcriptomes to clarify the inherent extra risks attributable to specific ART procedures. We discovered that IVF-ET seemed to introduce less disturbance into the infant epigenome than IVF-FET or ICSI-ET did. Furthermore, we noted approximately half of the DNA methylomic changes in ART-conceived offspring could be explained by parental background biases. Through removal of the parental effect, we confirmed that ART per se would introduce minor DNA methylation changes locally. More importantly, we found that ART-induced epigenomic alterations were highly enriched in the processes which might contribute to increased incidence of preeclampsia during pregnancy and metabolic syndrome in offspring. Overall, our study provides an epigenetic basis for the potential long-term health risks in ART-conceived offspring that reinforces the need to review all methods of human ART.

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Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human

Journal of Medical Genetics ◽

10.1136/jmg.2009.073189 ◽

2009 ◽

Vol 47 (6) ◽

pp. 371-376 ◽

Cited By ~ 76

Author(s):

S. Tierling ◽

N. Y. Souren ◽

J. Gries ◽

C. LoPorto ◽

M. Groth ◽

...

Keyword(s):

Dna Methylation ◽

Assisted Reproductive Technologies ◽

Reproductive Technologies

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Culture Medium and Sex Drive Epigenetic Reprogramming in Preimplantation Bovine Embryos

International Journal of Molecular Sciences ◽

10.3390/ijms22126426 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6426

Author(s):

Sebastian Canovas ◽

Elena Ivanova ◽

Meriem Hamdi ◽

Fernando Perez-Sanz ◽

Dimitrios Rizos ◽

...

Keyword(s):

Dna Methylation ◽

Assisted Reproductive Technologies ◽

Developmental Process ◽

Reproductive Technologies ◽

Sexually Dimorphic ◽

Element Analysis ◽

Global Methylation ◽

The Impact

Assisted reproductive technologies impact transcriptome and epigenome of embryos and can result in long-term phenotypic consequences. Whole-genome DNA methylation profiles from individual bovine blastocysts in vivo- and in vitro-derived (using three sources of protein: reproductive fluids, blood serum and bovine serum albumin) were generated. The impact of in vitro culture on DNA methylation was analyzed, and sex-specific methylation differences at blastocyst stage were uncovered. In vivo embryos showed the highest levels of methylation (29.5%), close to those produced in vitro with serum, whilst embryos produced in vitro with reproductive fluids or albumin showed less global methylation (25–25.4%). During repetitive element analysis, the serum group was the most affected. DNA methylation differences between in vivo and in vitro groups were more frequent in the first intron than in CpGi in promoters. Moreover, hierarchical cluster analysis showed that sex produced a stronger bias in the results than embryo origin. For each group, distance between male and female embryos varied, with in vivo blastocyst showing a lesser distance. Between the sexually dimorphic methylated tiles, which were biased to X-chromosome, critical factors for reproduction, developmental process, cell proliferation and DNA methylation machinery were included. These results support the idea that blastocysts show sexually-dimorphic DNA methylation patterns, and the known picture about the blastocyst methylome should be reconsidered.

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Author response: DNA methylation and gene expression changes derived from assisted reproductive technologies can be decreased by reproductive fluids

10.7554/elife.23670.027 ◽

2017 ◽

Author(s):

Sebastian Canovas ◽

Elena Ivanova ◽

Raquel Romar ◽

Soledad García-Martínez ◽

Cristina Soriano-Úbeda ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Assisted Reproductive Technologies ◽

Reproductive Technologies ◽

Author Response

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Are there subtle genome-wide epigenetic alterations in normal offspring conceived by assisted reproductive technologies?

Fertility and Sterility ◽

10.1016/j.fertnstert.2011.09.037 ◽

2011 ◽

Vol 96 (6) ◽

pp. 1306-1311 ◽

Cited By ~ 38

Author(s):

April Batcheller ◽

Eden Cardozo ◽

Marcy Maguire ◽

Alan H. DeCherney ◽

James H. Segars

Keyword(s):

Assisted Reproductive Technologies ◽

Reproductive Technologies ◽

Epigenetic Alterations ◽

Genome Wide ◽

Normal Offspring

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The influence of in vitro fertilization and embryo culture on the embryo epigenetic constituents and the possible consequences in the bovine model

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174417000125 ◽

2017 ◽

Vol 8 (4) ◽

pp. 411-417 ◽

Cited By ~ 9

Author(s):

M.-A. Sirard

Keyword(s):

Dna Methylation ◽

Assisted Reproductive Technologies ◽

Genetic Model ◽

Culture Media ◽

Reproductive Technologies ◽

The Body ◽

Model Systems ◽

Gene Perturbations

Medically assisted reproductive technologies, such as in vitro embryo production, are increasingly being used to palliate infertility. Eggs are produced following a hormonal regimen that stimulates the ovaries to produce a large number of oocytes. Collected oocytes are then fertilized in vitro and allowed to develop in vitro until they are either frozen or transferred to mothers. There are controversial reports on the adverse impacts of these technologies on early embryos and their potential long-term effects. Using newly developed technological platforms that enable global gene expression and global DNA methylation profiling, we evaluated gene perturbations caused by such artificial procedures. We know that cells in the early embryo produce all cells in the body and are able to respond to their in vitro environment. However, it is not known whether gene perturbations are part of a normal response to the environment or are due to distress and will have long-term impacts. While the mouse is an established genetic model used for quality control of culture media in clinics, the bovine is a large mono-ovulating mammal with similar embryonic kinetics as humans during the studied developmental window. These model systems are critical to understand the effects of assisted reproduction without the confounding impact of infertility and without the limitations imposed by the scarcity of donated human samples and ethical issues. The data presented in this review come mostly from our own experimentation, publications, and collaborations. Together they demonstrate that the in vitro environment has a significant impact on embryos at the transcriptomic level and at the DNA methylation level.

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On the origin of sperm epigenetic heterogeneity

Reproduction ◽

10.1530/rep-15-0436 ◽

2016 ◽

Vol 151 (5) ◽

pp. R71-R78 ◽

Cited By ~ 30

Author(s):

Sandra Laurentino ◽

Jennifer Borgmann ◽

Jörg Gromoll

Keyword(s):

Dna Methylation ◽

Stem Cell ◽

Cancer Biology ◽

Assisted Reproductive Technologies ◽

Human Sperm ◽

Cell Types ◽

Reproductive Technologies ◽

Aberrant Dna Methylation ◽

Near Future ◽

Sperm Epigenetics

AbstractThe influence of epigenetic modifications on reproduction and on the function of male germ cells has been thoroughly demonstrated. In particular, aberrant DNA methylation levels in sperm have been associated with abnormal sperm parameters, lower fertilization rates and impaired embryo development. Recent reports have indicated that human sperm might be epigenetically heterogeneous and that abnormal DNA methylation levels found in the sperm of infertile men could be due to the presence of sperm populations with different epigenetic quality. However, the origin and the contribution of different germ cell types to this suspected heterogeneity remain unclear. In this review, we focus on sperm epigenetics at the DNA methylation level and its importance in reproduction. We take into account the latest developments and hypotheses concerning the functional significance of epigenetic heterogeneity coming from the field of stem cell and cancer biology and discuss the potential importance and consequences of sperm epigenetic heterogeneity for reproduction, male (in)fertility and assisted reproductive technologies (ART). Based on the current information, we propose a model in which spermatogonial stem cell variability, either intrinsic or due to external factors (such as endocrine action and environmental stimuli), can lead to epigenetic sperm heterogeneity, sperm epimutations and male infertility. The elucidation of the precise causes for epimutations, the conception of adequate therapeutic options and the development of sperm selection technologies based on epigenetic quality should be regarded as crucial to the improvement of ART outcome in the near future.

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