Abstract
An increase in imprinting disorders in children conceived though assisted reproductive technologies (ARTs) has been the subject of several reports. The transmission of imprinting errors from the sperm of infertile fathers is believed to be a possible reason for the increased occurrence of these disorders. However, whether the imprinting alterations in sperm affect ART outcomes and the imprinting of offspring is unclear. In the current study, we analyzed the methylation of H19, SNRPN and KCNQ1OT1 by pyrosequencing sperm samples from 97 infertile patients and 31 proven fertile males as well as cord blood samples from 13 infantswho were conceived by infertile parents through intracytoplasmic sperm injection (ICSI) and 30 healthy newborns who were conceived naturally. After four cases were excluded owing to the lack of a sequencing signal, the infertile patients were subgrouped into normal (69 cases) and abnormal (24 cases) imprinting groups according to the reference range set by the control group. Between the groups, there were no significant differences in ART outcomes. Significantly different levels of methylation were detected in H19, but none of the imprinted genes were determined to be outside of the methylation reference range set by the values derived from the naturally conceived controls. Three CpG loci were found to be significantly hypomethylated in the maternally imprinted gene KCNQ1OT1 in two patients from the abnormal imprinting group, none of which were caused by sperm imprinting errors. In addition, the paternal H19 gene exhibited discrepant methylation patterns between the sperm controls and the cord blood controls. Our data suggest that increased imprinting errors in the sperm of infertile patients do not have an obvious influence on ART outcomes or the imprinting of offspring.
Highlights
It is estimated that more than 5 million infants resulting from assisted reproductive technologies (ARTs) have been born worldwide since 1978 when the first baby conceived via ART was born[1].the potential risks of ARTs are concerned for the effects of a genetic background of infertility as well as artificial operations performed at gametogenesis and in the early embryonic stages during which major epigenetic events occur[2].Adverse outcomes, including low birth weight and small size for gestational age, have been reported to occur at a greater frequency in infants conceived via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)[3,4,5,6].positive links between ARTs and imprinting disorders have been verified with strong evidence[7,8,9,10]
Recent studies have suggested that there is an increased incidence of typically rare imprinting disorders, including Beckwith-Wiedemann syndrome (BWS), Silver-Russell syndrome (SRS) and Angelman syndrome (AS), in children conceived through ARTs[7,8,9,10].The artificial treatments involved in ARTs at the time when major epigenetic events occur are believed to be responsible for the increase in imprinting disorders
We found that the methylation level of H19was significantly decreased in infants whose fathers produced sperm with imprinting errors (Table 3), suggesting an influence of paternal sperm methylation status on the imprinting of offspring
Summary
It is estimated that more than 5 million infants resulting from assisted reproductive technologies (ARTs) have been born worldwide since 1978 when the first baby conceived via ART was born[1].the potential risks of ARTs are concerned for the effects of a genetic background of infertility as well as artificial operations performed at gametogenesis and in the early embryonic stages during which major epigenetic events occur[2].Adverse outcomes, including low birth weight and small size for gestational age, have been reported to occur at a greater frequency in infants conceived via in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)[3,4,5,6].positive links between ARTs and imprinting disorders have been verified with strong evidence[7,8,9,10].Imprinting controls the allele-specific expression of genes based on parental origin by allele-specific methylation. A meta-analysis of 18 studies has shown that there is an increase in imprinting disorders in children conceived though IVF and ICSI, but insufficient evidence has been reported to verify an association between ARTs and methylation in imprinted genes[10].By contrast, accumulating experimental evidence has linked aberrant imprinting in sperm to male infertility[17,19,20,21,22,23,24,25,26,27].Imprinting is typically reset at germ cell stages, during which the methylation of imprinted genes is removed and re-established. The new, sex-specific imprinting patterns are typically maintained during early embryonic development when genome-wide demethylation and de novo methylation occur[18].The methylation errors in the sperm of infertile men may be transmitted to offspring through ARTs, which could be another possible explanation for the increase in imprinting disorders observed in ART children. Whether the imprinting errors in sperm affect ART outcomes and to what extent these errors are transmitted to offspring are unclear
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