Abstract
BackgroundAssisted reproductive technology (ART) might induce adverse pregnancy outcomes and increase the risk of metabolic diseases in offspring’ later life with unknown reasons. Here we evaluated the global methylation level and methylation profile of fetal tissue from elective terminations of pregnancy (ETP) after natural conception and multifetal pregnancy reduction (MFPR) after in vitro fertilization and embryo transfer (IVF-ET).ResultsGlobal methylation levels were comparable between the fetal tissue of ETP after natural conception group and MFPR after IVF-ET group. The methylation levels were lower in the hypermethylated regions of the MFPR group than in the ETP group, while the methylation levels were higher in the hypomethylated regions of the MFPR group. Heatmap visualization and hierarchical clustering of the candidate differentially methylated regions (DMRs) showed differences between the DMRs in the ETP and MFPR samples. We identified 196 differentially methylated regions that matched 164 genes between the ETP and MFPR groups. In the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, skeletal system morphogenesis and diabetes mellitus ranked first. Ingenuity Pathway Analysis (IPA) revealed 8 diseases and functional annotations associated with IVT-ET. In the MFPR group, the final validation showed lower methylation levels in gene bodies of bone morphogenetic protein 4 (BMP4), higher methylation levels in the 1st exon and 5′UTR of thyroid peroxidase (TPO), and higher methylation levels in TSS1500 and TSS200 of interleukin 1 beta (IL1B).ConclusionsART does not alter global DNA methylation level, but influences DNA methylation variation in specific regions of human fetus in the early stage of life. Further studies are warranted to clarify the potential role of DNA methylation alterations in the gene expression profile.
Highlights
The developmental origin of health and disease theory raised by David Barker points out that the period of early life is a window of developmental plasticity that is critically important for metabolic health in adulthood (Bateson et al, 2004)
To assess DNA methylation changes associated with assisted reproductive technology (ART), we performed epigenome-wide association studies with the Human Methylation 450k BeadChip array using fetal tissues from the elective terminations of pregnancy (ETP) and multifetal pregnancy reduction (MFPR) groups
There were no significant differences in the overall levels between the two groups, we found that the methylation level was lower in the true Differentially Methylated Regions (DMRs) of the MFPR group than in those of the ETP group on chromosome 7 but higher on chromosome 14 when stratified by different chromosomes
Summary
The developmental origin of health and disease theory raised by David Barker points out that the period of early life is a window of developmental plasticity that is critically important for metabolic health in adulthood (Bateson et al, 2004). Learning how abnormalities in the early developmental environment interact with the physiological processes, which, via developmental plasticity, determine the patterns of adult chronic diseases, especially epigenetic changes, is essential. A meta-analysis conducted by Pinborg et al (2013) concluded that subfertility is a major risk factor for adverse perinatal outcome in ART singletons; factors related to hormone stimulation and/or IVF methods per se may be involved. The raise of the developmental origins of adult disease has positioned low birth weight (LBW) as a significant health issue, which is tightly associated with increased risk of chronic metabolic diseases, such as metabolic syndrome, diabetes and cardiovascular disease, in later life (Lenfant, 2008; Stracquadanio and Ciotta, 2017). Assisted reproductive technology (ART) might induce adverse pregnancy outcomes and increase the risk of metabolic diseases in offspring’ later life with unknown reasons. We evaluated the global methylation level and methylation profile of fetal tissue from elective terminations of pregnancy (ETP) after natural conception and multifetal pregnancy reduction (MFPR) after in vitro fertilization and embryo transfer (IVF-ET)
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