Abstract
Children conceived through intracytoplasmic sperm injection (ICSI) have been reported to have a higher risk of many abnormalities and disorders, including autism and intellectual disability, which may be due to bypassing of the natural sperm selection process during ICSI. Zona pellucida (ZP)-bound spermatozoa (ZPBS) have normal morphology and nuclear DNA. Using these spermatozoa for ICSI results in better outcomes compared with conventional ICSI. However, differences besides morphology that exist between sperm selected by ZP and by an embryologist and whether these differences affect the risk of autism in offspring after ICSI are unclear. To explore these questions, we compared genome-wide DNA methylation profiles between ZPBS and manually selected spermatozoa (MSS)using single-cell bisulfite sequencing. Global DNA methylation levels were significantly lower in ZPBS than in MSS. Using gene ontology (GO) analysis, genes overlapping differentially methylated regions (DMRs) were enriched in biological processes involving neurogenesis. Furthermore, we found that 47.8% of autism candidate genes were associated with DMRs, compared with 37.1% of matched background genes (P<0.001). This was mainly because of the high proportion of autism candidate genes with bivalent chromatin structure. In conclusion, bivalent chromatin structure results in large differences in the methylation of autism genes between MSS and ZPBS. ICSI using MSS, which increases the risk of methylation mutations compared with ZPBS, may lead to a higher risk of autism in offspring.
Highlights
Infertility is one of the most common health disorders globally, affecting approximately 15% of the reproductive-aged population, with male infertility accounting for 30-50% of cases [1]
All of these men had normal semen parameters according to the WHO guidelines (2010) (Table 1).The genome-wide methylation level of each ZP-bound sperm (ZPBS) and manually selected spermatozoa (MSS) sample with 30-50 spermatozoa was detected by bisulfite sequencing
DNA methylation levels vary between different ejaculates from the same man and between high- and low-quality fractions of the same ejaculate [14]
Summary
Infertility is one of the most common health disorders globally, affecting approximately 15% of the reproductive-aged population, with male infertility accounting for 30-50% of cases [1]. In the United States, the use of ICSI for all non-male factor infertility cases increased from 15.4% in 1996 to 66.9% in 2012 [2]. ICSI may benefit couples by increasing the fertilization rate and decreasing the fertilization failure rate, there are concerns that the indiscriminate use of ICSI may lead to adverse health consequences for the offspring [3]. The risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profiles have been shown to be greater in infants born as a result of ICSI than in naturally conceived children [3]
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