Reduced meiotic recombination on the XY bivalent is correlated with an increased incidence of sex chromosome aneuploidy in men with non-obstructive azoospermia

Abstract

Both aberrant meiotic recombination and an increased frequency of sperm aneuploidy have been observed in infertile men. However, this association has not been demonstrated within individual men. The purpose of this study was to determine the association between the frequency of recombination observed in pachytene spermatocytes and the frequency of aneuploidy in sperm from the same infertile men. Testicular tissue from seven men with non-obstructive azoospermia (NOA) and six men undergoing vasectomy reversal (controls) underwent meiotic analysis. Recombination sites were recorded for individual chromosomes. Testicular and ejaculated sperm from NOA patients and controls, respectively, were tested for aneuploidy frequencies for chromosomes 9, 21, X and Y. There was a significant increase in the frequency of pachytene cells with at least one achiasmate bivalent in infertile men (12.4%) compared with controls (4.2%, P = 0.02). Infertile men also had a significantly higher frequency of sperm disomy than controls for chromosomes 21 (1.0% versus 0.24%, P = 0.001), XX (0.16% versus 0.03%, P = 0.004) and YY (0.12% versus 0.03%, P = 0.04). There was a significant correlation between meiotic cells with zero MLH1 foci in the sex body and total sex chromosome disomy (XX + YY + XY) in sperm from men with NOA (r = 0.79, P = 0.036).

Apoptosis mediated by phosphatidylserine externalization in the elimination of aneuploid germ cells during human spermatogenesis

“…There are no studies describing the possible molecular pathway of cell elimination associated with the meiotic Spindle Assembly Checkpoint (SAC). However, our results and others (Eaker et al, 2001;Ferguson et al, 2007;Sun et al, 2008) suggest that although the SAC checkpoint detects chromosome misalignments, it has a limited depletion efficiency leading to an increase in chromosomal abnormalities in post-reductional cells. Although statistical analysis in post-reductional germ cells did not show an association between the presence of chromosomal abnormalities and apoptosis, about half of these cells did not differentiate into spermatozoa.…”

“…Disruption of these processes are often linked to partial or total arrest of spermatogenesis (Gonsalves et al, 2004;Guichaoua et al, 2005;Topping et al, 2006;Ferguson et al, 2007;Sun et al, 2007) and increases of chromosomal abnormalities in spermatozoa (Hassold & Hunt, 2001;Egozcue et al, 2005;Ferguson et al, 2007;Martin, 2008;Sun et al, 2008). Moreover, there is a clear relationship between the presence of increased incidence of apoptotic germ cells and male infertility (Lin et al, 1997;Sun et al, 1997;Tesarik et al, 1998;Sakkas et al, 1999;Sinha Hikim & Swerdloff, 1999;Paasch et al, 2003;Wang et al, 2003;Chen et al, 2006;Zhang et al, 2008;Aitken et al, 2011).…”

Human Male Meiosis and Sperm Aneuploidies

“…The same patients exhibited an increase in the frequency of aneuploidies, specifically more sperm disomy than controls for chromosomes 21 (1.00% vs. 0.24%), X, (0.16% vs. 0.03%), and Y (0.12% vs. 0.03%). Further, a significant correlation was found between cells with sex vesicles lacking MLH1 foci and sex chromosome disomy in sperm (Sun et al, 2008a).…”

“…Additionally, immunocytogenetics can be combined with FISH to analyze recombination rates and crossover placement in individual chromosomes. While this assay also requires testicular biopsies to obtain material, pachytene has a long duration and nuclei are not as condensed as in diakinesis (Gonsalves et al, 2004(Gonsalves et al, , 2005Judis et al, 2004;Lynn et al, 2002;Ma et al, 2006;Sun et al, 2004aSun et al, , 2004bSun et al, , 2006Sun et al, , 2007Sun et al, , 2008aSun et al, , 2008b.…”

A sequential methodology that allows apoptotic cell sorting and FISH analysis in human testicular cells

“…It has been stated that these abnormalities can be recognized by meiotic checkpoints, which stop the process in order to repair the abnormality [Li et al 2009] or eliminate the affected cells via apoptosis [Hunt 2006;Hamer et al 2008]. Regardless, cells may also escape these checkpoints, leading to an increased risk of aneuploidy [Sun et al 2008]. Although a large number of studies have been undertaken in this field, none have focused on evaluating whether a direct relationship exists between the presence of the apoptotic process and chromosome abnormalities.…”