DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies)

Cánovas, Sebastián; Ross, Pablo J.; Kelsey, Gavin; Coy, Pilar

doi:10.1002/bies.201700106

Cited by 87 publications

(61 citation statements)

References 107 publications

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“…In a clinical context, this study has relevance in assisted reproductive techniques (ARTs) that are commonly used in human medicine and livestock breeding. Nowadays, children conceived using ART account for 2% of all births, which has brought the society a growing interest in their long-term health [ 12 ]. Moreover, in vitro production of bovine embryos is used worldwide for commercial purposes.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development

Wyck

Herrera

Requena

et al. 2018

Epigenetics & Chromatin

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BackgroundReactive oxygen species (ROS)-induced oxidative stress is well known to play a major role in male infertility. Sperm are sensitive to ROS damaging effects because as male germ cells form mature sperm they progressively lose the ability to repair DNA damage. However, how oxidative DNA lesions in sperm affect early embryonic development remains elusive.ResultsUsing cattle as model, we show that fertilization using sperm exposed to oxidative stress caused a major developmental arrest at the time of embryonic genome activation. The levels of DNA damage response did not directly correlate with the degree of developmental defects. The early cellular response for DNA damage, γH2AX, is already present at high levels in zygotes that progress normally in development and did not significantly increase at the paternal genome containing oxidative DNA lesions. Moreover, XRCC1, a factor implicated in the last step of base excision repair (BER) pathway, was recruited to the damaged paternal genome, indicating that the maternal BER machinery can repair these DNA lesions induced in sperm. Remarkably, the paternal genome with oxidative DNA lesions showed an impairment of zygotic active DNA demethylation, a process that previous studies linked to BER. Quantitative immunofluorescence analysis and ultrasensitive LC–MS-based measurements revealed that oxidative DNA lesions in sperm impair active DNA demethylation at paternal pronuclei, without affecting 5-hydroxymethylcytosine (5hmC), a 5-methylcytosine modification that has been implicated in paternal active DNA demethylation in mouse zygotes. Thus, other 5hmC-independent processes are implicated in active DNA demethylation in bovine embryos. The recruitment of XRCC1 to damaged paternal pronuclei indicates that oxidative DNA lesions drive BER to repair DNA at the expense of DNA demethylation. Finally, this study highlighted striking differences in DNA methylation dynamics between bovine and mouse zygotes that will facilitate the understanding of the dynamics of DNA methylation in early development.ConclusionsThe data demonstrate that oxidative stress in sperm has an impact not only on DNA integrity but also on the dynamics of epigenetic reprogramming, which may harm the paternal genetic and epigenetic contribution to the developing embryo and affect embryo development and embryo quality.Electronic supplementary materialThe online version of this article (10.1186/s13072-018-0224-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development

Wyck

Herrera

Requena

et al. 2018

Epigenetics & Chromatin

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“…Accordingly, we have shown in a mouse model that fertilization through ICSI using DNA‐damaged spermatozoa increases the incidence of behavioral disorders, overweight, organomegaly, cancer and premature aging in the adult offspring (Fernandez‐Gonzalez et al, ). Considering the heterogeneity of epigenetic marks present also in the spermatozoa (Jenkins et al, ) and that not all male epigenetic marks are erased after fertilization (Canovas, Ross, Kelsey, & Coy, ), male epigenetic modifications could be another source of long‐term effects associated with ART. Some authors have suggested a relationship between imprinting disorders in the offspring conceived through ART and changes at imprinted loci in the sperm of men with oligozoospermia (Filipponi & Feil, ; Kobayashi et al, ; Kobayashi et al, ).…”

Section: Long‐term and Transgenerational Effects Of Artmentioning

confidence: 99%

Embryo responses to stress induced by assisted reproductive technologies

Ramos‐Ibeas

Heras

Gómez-Redondo

et al. 2019

Molecular Reproduction Devel

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Assisted reproductive technology (ART) has led to the birth of millions of babies. In cattle, thousands of embryos are produced annually. However, since the introduction and widespread use of ART, negative effects on embryos and offspring are starting to emerge. Knowledge so far, mostly provided by animal models, indicates that suboptimal conditions during ART can affect embryo viability and quality, and may induce embryonic stress responses. These stress responses take the form of severe gene expression alterations or modifications in critical epigenetic marks established during early developmental stages that can persist after birth. Unfortunately, while developmental plasticity allows the embryo to survive these stressful conditions, such insult may lead to adult health problems and to long-term effects on offspring that could be transmitted to subsequent generations. In this review, we describe how in mice, livestock, and humans, besides affecting the development of the embryo itself, ART stressors may also have significant repercussions on offspring health and physiology. Finally, we argue the case that better control of stressors during ART will help improve embryo quality and offspring health. K E Y W O R D S assisted reproductive technologies, bovine, embryo, human, mouse, stress

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“…The mechanism by which blastocyst transfer alters gene expression is not well understood, though epigenetic dysregulation has been implicated (Choux et al 2015, Canovas et al 2017. To examine the potential sensitivity of the DEGs to changes in DNA methylation, we first evaluated whether the top 50 downregulated genes (fold change >3.1) and top 50 upregulated genes (fold change >6.7) contained intragenic CpG islands or proximal promoter CpG islands (within 20 kb of the gene) ( Fig.…”

Section: Dysregulation Of Dna Methylation At Proximal Promoter Regionmentioning

confidence: 99%

Blastocyst transfer in mice alters the placental transcriptome and growth

et al. 2020

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Assisted reproduction technologies (ARTs) are becoming increasingly common. Therefore, how these procedures influence gene regulation and foeto-placental development are important to explore. Here, we assess the effects of blastocyst transfer on mouse placental growth and transcriptome. C57Bl/6 blastocysts were transferred into uteri of B6D2F1 pseudopregnant females and dissected at embryonic day 10.5 for analysis. Compared to non-transferred controls, placentas from transferred conceptuses weighed less even though the embryos were larger on average. This suggested a compensatory increase in placental efficiency. RNA sequencing of whole male placentas revealed 543 differentially expressed genes (DEGs) after blastocyst transfer: 188 and 355 genes were downregulated and upregulated, respectively. DEGs were independently validated in male and female placentas. Bioinformatic analyses revealed that DEGs represented expression in all major placental cell types and included genes that are critical for placenta development and/or function. Furthermore, the direction of transcriptional change in response to blastocyst transfer implied an adaptive response to improve placental function to maintain foetal growth. Our analysis revealed that CpG methylation at regulatory regions of two DEGs was unchanged in female transferred placentas and that DEGs had fewer gene-associated CpG islands (within ~20 kb region) compared to the larger genome. These data suggested that altered methylation at proximal promoter regions might not lead to transcriptional disruption in transferred placentas. Genomic clustering of some DEGs warrants further investigation of long-range, cis-acting epigenetic mechanisms including histone modifications together with DNA methylation. We conclude that embryo transfer, a protocol required for ART, significantly impacts the placental transcriptome and growth.

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DNA Methylation in Embryo Development: Epigenetic Impact of ART (Assisted Reproductive Technologies)

Cited by 87 publications

References 107 publications

Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development

Oxidative stress in sperm affects the epigenetic reprogramming in early embryonic development

Embryo responses to stress induced by assisted reproductive technologies

Blastocyst transfer in mice alters the placental transcriptome and growth

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