Gonadotropin stimulation contributes to an increased incidence of epimutations in ICSI-derived mice

Eric De waal, Yukiko Yamazaki, Puraskar Ingale, Marisa S. Bartolomei, Ryuzo Yanagimachi, John R. McCarrey

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

We previously demonstrated that intracytoplasmic sperm injection (ICSI), a type of assisted reproductive technology (ART), can induce epimutations and/or epimutant phenotypes in somatic tissues of adult mice produced by this method. In the present study, we compared the occurrence of epimutations in mice produced by natural conception, ICSI and somatic cell nuclear transfer. Surprisingly, we observed the highest frequency of epimutations in somatic tissues from ICSI-derived mice. We also observed a delay in reprogramming of the maternal allele of the imprinted H19 gene in spermatogonia from juvenile ICSI-derived male mice. These observations led us to hypothesize that the exposure of the maternal gametic genome to exogenous gonadotropins during the endocrine stimulation of folliculogenesis (superovulation) may contribute to the disruption of the normal epigenetic programming of imprinted loci in somatic tissues and/or epigenetic reprogramming in the germ line of ensuing offspring. To test this hypothesis, we uncoupled superovulation from ICSI by subjecting female mice to gonadotropin stimulation and then allowing them to produce offspring by natural mating. We found that mice produced in this way also exhibited epimutations and/or epimutant phenotypes in somatic tissues and delayed epigenetic reprogramming in spermatogenic cells, providing evidence that gonadotropin stimulation contributes to the induction of epimutations during ART procedures. Our results suggest that gonadotropin stimulation protocols used in conjunction with ART procedures should be optimized to minimize the occurrence of epimutations in offspring produced by these methods.

Original languageEnglish (US)
Article numberdds287
Pages (from-to)4460-4472
Number of pages13
JournalHuman molecular genetics
Volume21
Issue number20
DOIs
StatePublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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