Epigenetics and assisted reproductive technology

Abstract

It is not clear whether there is an effect of assisted reproductive technology (ART) on the appearance of Beckwith Wiedemann syndrome (BWS), but Chang et al. (1Chang A.S. Moley K.H. Wangler M. Feinberg A.P. Debaun M.R. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology a case series of 19 patients.Fertil Steril. 2005; 83: 349-354Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar) conclude that there is no impact of the culture medium on BWS. It is true that BWS was found after IVF and early embryo culture with several different culture media human tubal fluid, P1 and G1. It is generally admitted that DNA hypomethylation and epigenetic problems of imprinting are clearly linked (1Chang A.S. Moley K.H. Wangler M. Feinberg A.P. Debaun M.R. Association between Beckwith-Wiedemann syndrome and assisted reproductive technology a case series of 19 patients.Fertil Steril. 2005; 83: 349-354Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 2Diaz-Meyer N. Day C.D. Khatod K. Maher E.R. Cooper W. Reik W. et al.Silencing of CDKN1C (p57KIP2) is associated with hypomethylation at KvDMR1 in Beckwith-Wiedemann syndrome.J Med Genet. 2003; 40: 797-801Crossref PubMed Scopus (130) Google Scholar) and mainly controlled by SAM (S adenosylmethionine) produced by the SAM synthetase. S adenosylmethionine synthetase is active in the mouse and human oocytes and early embryo (3Menezo Y. Khatchadourian C. Gharrib Greenland T. Sarda N. Regulation of S-adenosyl methionine synthesis in the mouse embryo.Life Sci. 1989; 44: 1601-1609Crossref PubMed Scopus (55) Google Scholar) and requires methionine for its synthesis. A methyl group is released (at CpG) and S adenosylhomocysteine is formed. In a recent article concerning BWS, Niemitz and Feinberg stated that “the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes” (4Niemitz E.L. Feinberg A.P. Epigenetics and assisted reproductive technology a call for investigation.Am J Human Genet. 2004; 74: 599-609Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar). The methionine content is the critical difference that can affect DNA methylation and imprinting (4Niemitz E.L. Feinberg A.P. Epigenetics and assisted reproductive technology a call for investigation.Am J Human Genet. 2004; 74: 599-609Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 5Wolff G.L. Kodell R.L. Moore S.R. Cooney C.A. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice.FASEB J. 1998; 12: 949-957Crossref PubMed Scopus (846) Google Scholar). Methionine is actively transported in all animal and human oocytes and in early preimplantation embryo (3Menezo Y. Khatchadourian C. Gharrib Greenland T. Sarda N. Regulation of S-adenosyl methionine synthesis in the mouse embryo.Life Sci. 1989; 44: 1601-1609Crossref PubMed Scopus (55) Google Scholar). In mouse embryos, silent paternal alleles of H19, Igf2, Grb10, and Grb7 are aberrantly expressed and hypomethylated in simplex media but not media with amino acids (6Khosla S. Dean W. Reik W. Feil R. Culture of preimplantation embryos and its long-term effect on gene expression and phenotype.Hum Reprod Update. 2001; 7: 419-427Crossref PubMed Scopus (213) Google Scholar). All the media mentioned in the Chang et al. article contain no methionine, at least during the first days, before the decrease in DNA methyl transferase activity. It can thus be expected that patients with a borderline endogenous amino acid pool might have depletion of SAM and thus methylation problems. It would be interesting to note whether there is a difference when methionine is added in the culture media. Again, at this level, the question is not whether ART leads to BWS. Controlled ovarian stimulation might perturb oocyte quality and further epigenetic regulation, as is often observed in animal species. Maternal age and the borderline quality of the endogenous amino acid pool of the resulting oocyte might also affect regulation of the methylation process. However, in ART, some media, because of the impact of methionine on methylation, could be more problematic than others. Reply of the AuthorsFertility and SterilityVol. 85Issue 1PreviewIn our article, we conclude that one specific type of media did not predominate among the cases and that we did not have a large enough sample size to find a common factor. We did not conclude that there is no impact of the culture media on Beckwith-Wiedemann syndrome (BWS), as Dr. Menezo deduced. It is possible that methionine content of the media could affect normal imprinting at this stage, as has been suggested. The G2 and Cook’s sequential media, however, both contain methionine and were two of the five media recorded among the patients’ IVF protocols. Full-Text PDF