Association of In Vitro Fertilization with Beckwith-Wiedemann Syndrome and Epigenetic Alterations of LIT1 and H19

DeBaun, Michael R.; Niemitz, Emily; Feinberg, Andrew P.

doi:10.1086/346031

Cited by 862 publications

(593 citation statements)

References 22 publications

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“…89,90 A number of studies report that BWS and AS cases are overrepresented in children born through ART. 42,[91][92][93][94][95] However, other studies did not find evidence for increased risk for these diseases, 96,97 and the relationship between ART and imprinting disorders remains to be established. 98,99 Recently, it was reported that the expression state of the imprinted Dlk1-Dio3 cluster on mouse chromosome 12 is often altered in iPS cells.…”

Section: Molar Pregnancy Infertility Assisted Reproductive Technolomentioning

confidence: 97%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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Genomic imprinting is an epigenetic gene-marking phenomenon that occurs in the germline, whereby genes are expressed from only one of the two parental copies in embryos and adults. Imprinting is essential for normal mammalian development and its disruption can cause various developmental defects and diseases. The process of imprinting in the germline involves DNA methylation of the imprint control regions (ICRs), and resulting parental-specific methylation imprints are maintained in the zygote and act as the marks controlling imprinted gene expression. Recent studies in mice have revealed new factors involved in imprint establishment during gametogenesis and maintenance during early development. Clinical studies have identified cases of imprinting disorders where involvement of factors shared by multiple ICRs for establishment or maintenance is suspected. These include Beckwith-Wiedemann syndrome, transient neonatal diabetes, Silver-Russell syndrome and others. More severe disruptions can lead to recurrent molar pregnancy, miscarriage or infertility. Imprinting defects may also occur during assisted reproductive technology or cell reprogramming. In this review, we summarize our current knowledge on the mechanisms of imprint establishment and maintenance, and discuss the relationship with various human disorders.

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Section: Molar Pregnancy Infertility Assisted Reproductive Technolomentioning

confidence: 97%

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Tomizawa

Sasaki

2012

J Hum Genet

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“…3 Several reports have supported the idea that artificial reproductive techniques (ARTs) would favour the acquisition of imprinting errors. [4][5][6][7][8] Epigenetic abnormalities in ART could be related to parental infertility, corresponding to imprinting errors in the gametes, transmitted at fertilisation, or to in vitro manipulation of gametes and embryos. 9 Therefore, looking for imprinting defects in embryos that failed to develop normally and in the gametes would provide information on whether unsuitable imprint in the gametes could be transmitted and associated with developmental arrest.…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, methylation on the paternal DMR prevents the binding of CTCF, permitting IGF2 expression. Hypermethylation of H19 maternal allele is linked to Beckwith-Wiedemann syndrome (BWS) in some patients, 4 whereas hypomethylation of the paternal allele is associated with Silver-Russell syndrome, 14 both syndromes showing opposed growth disorders.…”

Section: Introductionmentioning

confidence: 99%

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

et al. 2011

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ART is suspected to generate increased imprinting errors in the lineage. Following an intra cytoplasmic sperm injection (ICSI) procedure, a certain number of embryos fail to develop normally and imprinting disorders may be associated to the developmental failure. To evaluate this hypothesis, we analysed the methylation profile of H19DMR, a paternally imprinting control region, in high-graded blastocysts, in embryos showing developmental anomalies, in the matching sperm and in oocytes of the concerned couples when they were available. Significant hypomethylation of the paternal allele was observed in half of the embryos, independently of the stage at which they were arrested (morula, compacted morula, pre blastocyst or BC-graded blastocysts). Conversely, some embryos showed significant methylation on the maternal allele, whereas few others showed both hypomethylation of the paternal allele and abnormal methylation of the maternal allele. The matching sperm at the origin of the embryos exhibited normal methylated H19 patterns. Thus, hypomethylation of the paternal allele in the embryos does not seem inherited from the sperm but likely reflects instability of the imprint during the demethylating process, which occurred in the early embryo. Analysis of a few oocytes suggests that the defect in erasure of the paternal imprint in the maternal germ line may be responsible for the residual methylation of the maternal allele in some embryos. None of these imprinting alterations could be related to a particular stage of developmental arrest; compared with high-grade blastocysts, embryos with developmental failure are more likely to have abnormal imprinting at H19 (Po0.05).

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“…Changes in DNA methylation profiles in spermatozoa is found in association with oligozoospermia, with some studies indicating up to 46 % of men with reduced sperm counts have altered DNA methylation profiles in their sperm [14][15][16][17]. Hypomethylation of normally hypermethylated paternally imprinted loci is associated with various cancers, disorders of growth and metabolism such as BeckwithWiedemann and disorders in neurodevelopment, cognition, and behaviour [18,19]. Our data reports a normal pregnancy that have resulted from germ cells exposed 32 months ago to an alkylating agent.…”

Section: Discussionmentioning

confidence: 99%

Effect of temozolomide on male gametes: an epigenetic risk to the offspring?

Berthaut

Montjean

Dessolle

et al. 2013

J Assist Reprod Genet

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Introduction Temozolomide is an oral alkylating agent with proven efficacy in recurrent high-grade glioma. The antitumour activity of this molecule is attributed to the inhibition of replication through DNA methylation. However, this methylation may also perturb other DNA-dependent processes, such as spermatogenesis. The ability to father a child may be affected by having this treatment. Here we report a pregnancy and a baby born after 6 cures of temozolomide. Methods The quality of gametes of the father has been studied through these cures and after the cessation of treatment. Sperm parameters, chromosomal content and epigenetic profiles of H19, MEST and MGMT have been analysed.Results Sperm counts decrease significantly and hypomethylation of the H19 locus increase with time even staying in the normal range. Conclusion This is the first report of an epigenetic modification in sperm after temozolomide treatment suggesting a potential risk for the offspring. A sperm cryopreservation before the initiation of temozolomide treatment should be recommended.

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Association of In Vitro Fertilization with Beckwith-Wiedemann Syndrome and Epigenetic Alterations of LIT1 and H19

Cited by 862 publications

References 22 publications

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Genomic imprinting and its relevance to congenital disease, infertility, molar pregnancy and induced pluripotent stem cell

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

Effect of temozolomide on male gametes: an epigenetic risk to the offspring?

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