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



None.



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.
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Molly S
MS
Estill
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Jay M
JM
Bolnick
USDA/ARS Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Robert A
RA
Waterland
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan.
Alan D
AD
Bolnick
Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia.
Michael P
MP
Diamond
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; Center for Molecular Medicine and Genetics, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: steve@compbio.med.wayne.edu.
Stephen A
SA
Krawetz
D016022:Case-Control Studies; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D059788:Dried Blood Spot Testing; D004624:Embryo Transfer / Q000009:adverse effects*; D005260:Female; D005298:Fertility; D005307:Fertilization in Vitro / Q000009:adverse effects*; D006801:Humans; D007231:Infant, Newborn; D007246:Infertility / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D007315:Insemination, Artificial / Q000009:adverse effects; D008297:Male; D015997:Neonatal Screening / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D020554:Sperm Injections, Intracytoplasmic / Q000009:adverse effects; D016896:Treatment Outcome
D004247:DNA
450k; ART; ICSI; epialleles; epigenetics