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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #337854
Title: Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants

Author
item ESTILL, MOLLY - Wayne State University
item BOLNICK, JAY - Wayne State University
item WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)
item BOLNICK, ALAN - Wayne State University
item DIAMOND, MICHAEL - Augusta University
item KRAWETZ, STEPHEN - Wayne State University

Submitted to: Fertility and Sterility
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/10/2016
Publication Date: 9/1/2016
Citation: Estill, M.S., Bolnick, J.M., Waterland, R.A., Bolnick, A.D., Diamond, M.P., Krawetz, S.A. 2016. Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants. Fertility and Sterility. 106(3):629-639e10.

Interpretive Summary: "Epigenetics" describes the study of the molecular mechanisms that stabilize gene expression potential in different tissues and cell types; one of these mechanisms, DNA methylation, is recognized as the most stable. Just as genetic variation among individuals can contribute to risk of disease, there is great interest in understanding to what extent individual epigenetic variation is a factor in human disease. Previous studies in mice and humans have shown that environmental factors during early development can affect epigenetic development; special genomic regions called 'metastable epialleles' are particularly sensitive to such effects. During assisted reproductive technology (i.e. in vitro fertilization), the human embryo is cultured in a synthetic culture medium for several days before being transferred to the recipient woman's uterus. We tested whether exposure to this artificial environment induces epigenetic changes in the baby. Using DNA from dried blood spots that are collected at birth for newborn testing, we performed genome-scale DNA methylation profiling, and found that indeed, children conceived by assisted reproductive technology there are alterations in DNA methylation, particularly at regions we previously identified as putative metastable epialleles. The long-term consequences of these induced epigenetic alterations will need to be evaluated in future studies.

Technical Abstract: To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring. Microarray analysis of DNA methylation in archived neonatal bloodspots of in vitro fertilization (IVF)/ICSI-conceived children compared with controls born to fertile and infertile parents. Academic research laboratory. Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer. There were none interventions. The Illumina Infinium HumanMethylation450k BeadChip assay determined genome-wide DNA methylation. Methylation differences between conception groups were detected using a Bioconductor package, ChAMP, in conjunction with Adjacent Site Clustering (A-clustering). The methylation profiles of assisted reproductive technology and IUI newborns were dramatically different from those of naturally (in vivo) conceived newborns. Interestingly, the profiles of ICSI-frozen (FET) and IUI infants were strikingly similar, suggesting that cryopreservation may temper some of the epigenetic aberrations induced by IVF or ICSI. The DNA methylation changes associated with IVF/ICSI culture conditions and/or parental infertility were detected at metastable epialleles, suggesting a lasting impact on a child's epigenome.Both infertility and ICSI alter DNA methylation at specific genomic loci, an effect that is mitigated to some extent by FET. The impact of assisted reproductive technology and/or fertility status on metastable epialleles in humans was uncovered. This study provides an expanded set of loci for future investigations on IVF populations.