Whole-Genome Methylation Analysis Revealed ART-Specific DNA Methylation Pattern of Neuro- and Immune-System Pathways in Chinese Human Neonates

Abstract

The DNA methylation of human offspring can change due to the use of assisted reproductive technology (ART). In order to find the differentially methylated regions (DMRs) in ART newborns, cord blood maternal cell contamination and parent DNA methylation background, which will add noise to the real difference, must be removed. We analyzed newborns’ heel blood from six families to identify the DMRs between ART and natural pregnancy newborns, and the genetic model of methylation was explored, meanwhile we analyzed 32 samples of umbilical cord blood of infants born with ART and those of normal pregnancy to confirm which differences are consistent with cord blood data. The DNA methylation level was lower in ART-assisted offspring at the whole genome-wide level. Differentially methylated sites, DMRs, and cord blood differentially expressed genes were enriched in the important pathways of the immune system and nervous system, the genetic patterns of DNA methylation could be changed in the ART group. A total of three imprinted genes and 28 housekeeping genes which were involved in the nervous and immune systems were significant different between the two groups, six of them were detected both in heel blood and cord blood. We concluded that there is an ART-specific DNA methylation pattern involved in neuro- and immune-system pathways of human ART neonates, providing an epigenetic basis for the potential long-term health risks in ART-conceived neonates.

DNA Methylation in Offspring Conceived after Assisted Reproductive Techniques: A Systematic Review and Meta-Analysis

“…In another study, hypermethylation was observed in the LUMA assay and hypomethylation in the LINE1 assessment in the ART group compared to the SC group [ 38 ]. However, in other eight studies, no difference was observed between global methylation rates in the ART and control groups [ 27 , 31 , 32 , 35 , 46 , 49 , 54 , 56 ].…”

“…On the other hand, with regard to maternal age, 14 of the 50 included studies did not report the maternal age and, therefore, did not consider it in the adjusted analysis [ 25 , 34 , 36 , 48 , 50 , 54 , 55 , 60 , 62 , 63 , 65 , 69 , 72 , 73 ]. However, in four other studies, although reported, the analysis would not appear to be corrected by parental age [ 44 , 46 , 66 , 67 ].…”

Effects of assisted reproductive technology on gene expression in heart and spleen tissues of adult offspring mouse

“…DNA methylation changes occur not only at the whole genome level, but also in multiple imprinted genes, increasing the risk of cardiac metabolic abnormalities ( 24 ). There are specific DNA methylation patterns in ART neonates, including imprinted and housekeeping genes, involving neural and immune system pathways ( 25 ). Studies have shown that ovulation induction results in imprinting errors and cross-generational effects ( 26 ).…”

Update on the Epigenomic Implication of Embryo Cryopreservation Methods Applied in Assisted Reproductive Technologies With Potential Long-Term Health Effects

“…A multi-omic analysis based on cord blood of different IVF techniques, revealed a higher number of differentially expressed genes in children born after FET ( Wei Chen et al, 2020 ; Zongzhi Liu et al, 2021 ). A study based on mice models reported differences induced by vitrification in transcriptional profile of microRNAs (miRNAs) over biogenesis pathway when cryopreservation was performed during the earlier stages of preimplantation embryos ( Azizi et al, 2021 ); by contrast in later stages, it involves miRNAs related to embryo implantation ( Zhao et al, 2015 ).…”