Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1.
Aberrant imprinting in spermatozoa in a subset of infertile men has been postulated to be a risk factor for congenital diseases in children conceived via assisted reproduction techniques (ART). Studies in clinically well characterized large cohorts, however, have been missing. Using bisulfite sequencing, we determined the degree of methylation of the IGF2/H19 imprinting control region 1 (ICR1) and MEST differentially methylated regions in swim-up purified spermatozoa from 148 idiopathic infertile men and 33 normozoospermic controls. All control individuals had a high degree of IGF2/H19 ICR1 and a low degree of MEST methylation. Low sperm counts were clearly associated with IGF2/H19 ICR1 hypomethylation and, even stronger, with MEST hypermethylation. MEST hypermethylation, but not IGF2/H19 ICR1 hypomethylation was found in idiopathic infertile men with progressive sperm motility below 40% and bad sperm morphology below 5% normal spermatozoa. Ageing could be ruled out as a cause for the observed methylation defects. Sequence analysis of the CTCFL gene in peripheral blood DNA from 20 men with severe methylation defects revealed several polymorphisms, but no bona fide mutation. We conclude that idiopathic male infertility is strongly associated with imprinting defects at IGF2/H19 ICR1 and MEST, with aberrant MEST methylation being a strong indicator for sperm quality. The male germ cell thus represents a potential source for aberrant epigenetic features in children conceived via ART.
Poplinski
A
A
Centre of Reproductive Medicine and Andrology, 48149 Münster, Germany.
Tüttelmann
F
F
Kanber
D
D
Horsthemke
B
B
Gromoll
J
J
D000328:Adult; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008297:Male; D008745:Methylation; D011506:Proteins / Q000378:metabolism*; D013076:Sperm Count; D013081:Sperm Motility / Q000502:physiology
C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; C035170:IGF2 protein, human; D011506:Proteins; C103637:mesoderm specific transcript protein; D007335:Insulin-Like Growth Factor II