The Consequences of Somatic Sex Chromosomal Abnormalities on Meiosis and Sperm Production in Infertile Men

Homologous chromosome pairing (synapsis) and DNA exchange (recombination) during meiosis govern chromosome segregation. Our recent work showed the correlation of a lack of recombination on the sex chromosomes (XY) with increased XY disomy in the sperm of infertile men. Carriers of XY abnormalities may face more segregation errors due to errors in XY pairing, possibly leading to increased levels of aneuploid sperm, which may not be suitable for use in ICSI. This study aims to investigate the meiotic behavior and sperm aneuploidy rates in three infertile men with mosaic or abnormal sex chromosomal karyotypes. We obtained ejaculate sperm from a 47,XYY infertile man and testicular tissue from a 45,X(50%)/46,XY and a 47,XXY(10%)/46,XY infertile man. Testicular tissue from ten 46,XY fertile men undergoing vasectomy reversal was used as control. We used fluorescence immunostaining to visualize the synaptonemal complex and MLH1 proteins in order to assess the chromosome pairing and global recombination, respectively. We also analyzed the meiotic XY patterns. Sperm aneuploidy rates were determined using fluorescence in situ hybridization. Mann-Whitney Test and Fisher Test were used for statistical analysis. The meiotic transcriptional activity of the XY body was also examined using immunostaining in the 45,X/46,XY man. 22% of spermatocytes (n=45) in the 47,XYY man were 46,XY, where 50% had unpaired XY. 78% of spermatocytes were 47,XYY. In the 45,X/46,XY man, 75% of spermatocytes (n=101) were 46,XY, where 16% had unpaired XY. Only 25% of spermatocytes were 45,X. The unpaired XY in the 45,X/46,XY man had abnormal transcriptional inactivation. On the other hand, all of the spermatocytes in the 47,XXY/46,XY man were 46,XY. The mosaic carriers showed normal synaptic and recombination rates compared to controls (P>0.05, Mann-Whitney Test). All three carriers showed elevated rates of XY disomy and sex nullisomy in the sperm compared to controls (P < 0.01, Fisher Test). We are the first to study meiotic behaviors in depth in a 45,X/46,XY man. We unprecedentedly noted unpaired XY in the 45,X/46,XY and 47,XYY men, suggesting a new mechanism for arrest of these cells. We found that the meiotic cell constitution in carriers of XY abnormalities may be different than the somatic karyotype, potentially due to cell arrest pre-meiosis. The increased rates of sperm aneuploidy in the carriers were within the range found in 46,XY infertile men1-9. The important clinical relevance of our work is that infertile men with XY abnormalities may produce sperm with primarily normal chromosomal constitution, which makes the extraction of normal sperm for ICSI possible in men with similar karyotypes.