Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants.

<bold>Objective: </bold>To evaluate the effect of infertility and intracytoplasmic sperm injection (ICSI) on DNA methylation of offspring.<bold>Design: </bold>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.<bold>Setting: </bold>Academic research laboratory.<bold>Patient(s): </bold>Neonatal blood spots of 137 newborns conceived spontaneously, through intrauterine insemination (IUI), or through ICSI using fresh or cryopreserved (frozen) embryo transfer.<bold>Intervention(s): </bold>None.<bold>Main Outcome Measure(s): </bold>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).<bold>Result(s): </bold>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.<bold>Conclusion(s): </bold>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. [ABSTRACT FROM AUTHOR]