Hum. Reprod. Advance Access originally published online on April 24, 2008
Human Reproduction 2008 23(7):1679-1683; doi:10.1093/humrep/den126
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A comparison of sperm aneuploidy rates between infertile men with normal and abnormal karyotypes
Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, Canada
1 Correspondence address. Department of Obstetrics and Gynaecology, Room D414B, BC Women's Hospital and Health Centre, University of British Columbia, D6-4500 Oak Street, Vancouver, British Columbia, Canada V6H 3N1. Tel: +1-604-875-2345 ext. 5686; Fax: +1-604-875-2722; E-mail: sai{at}interchange.ubc.ca
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Abstract |
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BACKGROUND: Abnormal semen parameters in chromosomally normal men are an indicator of an increased risk of sperm aneuploidy. Male carriers of chromosomal rearrangements may also display an increase in sperm aneuploidy for chromosomes not involved in the rearrangement, known as an interchromosomal effect (ICE), and this may be related to the impaired semen parameters of these men.
METHODS: Aneuploidy was examined in ejaculate sperm from 27 men: 8 carriers of chromosomal rearrangements with severe oligoasthenoteratozoospermia (OAT) or severe teratozoospermia; 10 chromosomally normal men with similarly abnormal semen parameters; and 9 proven fertile men with normal semen parameters. Fluorescence in situ hybridization was used to examine aneuploidy for chromosomes 13, 18, 21, X and Y.
RESULTS: We observed evidence of an ICE in three of the eight carriers of chromosomal rearrangements. However, men who were chromosomally normal but had severe OAT more frequently displayed increased disomy rates. Although autosomal disomy rates were only modestly increased in some of these men, increased XY disomy ranged from slight to extreme (up to a 100-fold increase).
CONCLUSIONS: Despite their similar semen parameters, infertile men with normal karyotypes displayed more frequent increases in sperm aneuploidy, particularly involving the sex chromosomes, than infertile men who were carriers of chromosomal rearrangements. The difference in the magnitude and type of sperm aneuploidy between the two infertile groups is likely related to the different causes of infertility.
Key words: interchromosomal effect/sperm aneuploidy/male infertility/chromosomal rearrangements/FISH
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Introduction |
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It has long been established that the presence of a chromosomal rearrangement increases the likelihood of meiotic disjunction errors involving the rearranged chromosomes. However, it has been suggested that such rearrangements can also influence the segregation of uninvolved chromosomes. As a result, an increased aneuploidy in the sperm may be observed for chromosomes not involved in the rearrangement, known as an interchromosomal effect (ICE). An ICE was first described in humans by Lejeune (1963)
, and chromosome translocations have been shown to affect meiotic segregation of uninvolved chromosomes in mice (Ford and Evans, 1973) and in Drosophila (Grell, 1971). However, in humans, the existence of an ICE has remained a source of controversy with some studies observing such an effect (Blanco et al., 2000; Anton et al., 2004; Douet-Guilbert et al., 2005; Machev et al., 2005), whereas others have not (Honda et al., 1999; Rives et al., 2003).
Confirming both the existence and magnitude of an ICE has been further complicated by the fact that male carriers of chromosomal rearrangements often display abnormal semen parameters, which in itself is an indicator of elevated rates of sperm aneuploidy. Several studies on sperm from infertile men with normal 46,XY karyotypes have shown that men with abnormal semen parameters are at an increased risk of producing aneuploid sperm (Pang et al., 1999; Vegetti et al., 2000; Martin et al., 2003). This observed increase in sperm aneuploidy from infertile men has been further supported by the increase in de novo chromosomal abnormalities of paternal origin after intracytoplasmic sperm injection (ICSI) (Van Opstal et al., 1997; Bonduelle et al., 2002; Tang et al., 2004).
Several studies have examined sperm aneuploidy in translocation carriers with normal semen parameters and found no existence of an ICE (Pellestor et al., 2001; Oliver-Bonet et al., 2004; Douet-Guilbert et al., 2005), further suggesting that the presence of an ICE may be associated with abnormal semen parameters. However, meiotic studies on chromosomally normal men have suggested that defective recombination contributes to both the infertility and increased sperm aneuploidy in men with impaired spermatogenesis (Gonsalves et al., 2004; Ma et al., 2006; Ferguson et al., 2007). Conversely, meiotic studies on carriers of reciprocal translocations suggest that defective recombination is not a contributing factor to infertility in men with chromosomal rearrangements (Oliver-Bonet et al., 2005; Pigozzi et al., 2005). It is likely that the existence of an ICE in male carriers of chromosomal rearrangements, and the increased sperm aneuploidy in karyotypically normal men with abnormal semen parameters, may be two distinct, unrelated phenomena. Thus, the magnitude of sperm aneuploidy, and therefore the risk of a chromosomal abnormality after ICSI, is likely to differ between the two infertile groups.
In this study, we used fluorescence in situ hybridization (FISH) on decondensed sperm nuclei to examine the existence of an ICE in ejaculate samples from eight infertile carriers of previously unstudied structural chromosomal abnormalities, including five translocations, two inversions and a carrier of a complex chromosomal rearrangement. In order to compare the magnitude of sperm aneuploidy in carriers of rearrangements to that observed in chromosomally normal men with similar semen parameters, FISH was also performed on sperm from 10 karyotypically normal men with severe oligoasthenoteratozoospermia (OAT). We studied the segregation of chromosomes 13, 18, 21, X and Y, as aneuploidies for these chromosomes are a major cause of spontaneous abortion and congenital malformations in live births.
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Clinical information
The 8 carriers of chromosomal rearrangements and 10 men with OAT were ascertained via fertility clinic workups for primary infertility. All patients had history of infertility ranging from 2 to 6 years. Of the carriers of chromosomal abnormalities, seven out of eight carriers had severe OAT with sperm counts ranging from a few hundred to 3.8 million per millimetre, whereas one had only severe abnormal sperm morphology (<5%) with normal sperm count and motility (Table I). Serum gonadotrophins and testosterone were normal in all patients. All patients were carriers of chromosomal rearrangements based on clinical cytogenetic reports including two Robersonian translocations [45,XY,rob(13;21)(q10;q10) and 46,XY,rob(13;21)(p11.1;p11.1),+mar], three reciprocal translocations [t(9;22)(p13.1;q13.2), t(4;15)(p12;p11.1) and t(6;21)(q16;q21)], a t(1;2;10)(1qter->1p35.1::10q26.13->1-qter; 2pter->2q21.3::1p35.1->1pter; 10pter->10q11.23::10q24.33->10q11.23::2q21.2->2qter) complex chromosomal rearrangement and two inversions [paracentric inv(5)(q22.1;q23.2) and pericentric inv(Y)]. The 45,XY,rob(13;21) case was previously reported on in Hatakeyama et al. (2006)
. All OAT patients had normal karyotypes and displayed semen parameters with very low sperm count (<5 x 106/ml), low motility (<50%) and low normal morphology (<30%), according to WHO (1999) guidelines. Sperm aneuploidy and the ICSI outcome of patient OAT9 was reported previously (Tang et al., 2004). The mean age of the carriers of chromosomal rearrangements was 40.1 years (range: 32–53), whereas the mean age of the OAT patients was 38.1 years (range: 29–50). Nine men of proven normal fertility (naturally fathered at least one child) with normal somatic karyotypes and normal semen analyses were recruited to form the control group of this study. The mean age of the normal fertile control donors was 31.6 years (range: 29–33). This study was approved by the UBC Clinical Ethical Board prior to the initiation of the experiments.
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FISH analysis
The methods of sperm preparation, probe hybridization and FISH analysis were described previously (Tang et al., 2004
). Briefly, sperm were fixed onto glass slides (with 3:1 methanol/acetic acid) washed in 2x SSC (saline-sodium citrate solution) and incubated in dithiothreitol. Triple-colour FISH, with 
-satellite DNA probes for chromosomes 18 (SpectrumAqua), X (SpectrumGreen) and Y (SpectrumOrange), and dual-colour FISH, with probes for chromosomes 13 (SpectrumGreen) and 21 (SpectrumOrange) (Vysis Inc., Downers Grove, IL, USA) were used for both patient and control samples. Hybridization procedures followed the manufacturer's protocols. Only sperm with intact head and tail morphology, and within an area of the slide where consistent hybridization was evident, were scored. We attempted to score a minimum of 10 000 sperm for each probe set for each individual; however, in some men only several hundred to several thousand sperm could be found in the semen samples.
Statistical analysis
Data from chromosomally normal fertile men were pooled into a control group to determine a baseline rate of sperm aneuploidy. Disomy rates for individual men from the two infertile groups were compared with the pooled group of control men using the Chi-square test. All statistical analyses were performed using the GraphPad Prism V5.0 program (GraphPad Software, San Diego, CA, USA). A value of P < 0.05 was considered significant.
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Results |
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Using dual-colour FISH for chromosomes 13 and 21, and triple-colour FISH for chromosomes 18, X and Y, a total of 317 584 sperm from the two infertile groups and 182 387 sperm from nine normal control men were scored. Hybridization efficiencies of the FISH probes ranged from 98.74 to 99.95%. Out of the eight carriers of chromosomal rearrangements, three men showed significantly increased disomy for at least one chromosome when compared with the control group (Table II). The carrier of the t(1;2;10) complex chromosomal rearrangement showed a significant increase in disomies 13 and 21 (P < 0.001; Chi-square test); the carrier of the t(9;22) showed an increase in disomy 21 (P < 0.001; Chi-square test); and the carrier of the t(6;21) translocation showed an increase in disomy 13 (P < 0.001; Chi-square test) (Table II). None of the carriers of chromosomal rearrangements showed a significant increase in the rates of sex chromosome disomy or disomy 18. Among the 10 chromosomally normal men with severe OAT, 8 men showed a significant increase in XY disomy and 3 men showed an increase in XX or YY disomy (Table II). Four men with severe OAT showed a significant increase in disomy 18, three men showed a significant increase in disomy 13 and three men showed an increase in disomy 21 (Table II). Of the 10 men with severe OAT, only 2 (OAT10; OAT16) had disomy rates that were not significantly increased when compared with the control group, whereas the other 8 men showed increased disomy for at least one of the chromosomes studied.
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Discussion |
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The aim of this study was to determine if carriers of structural chromosomal abnormalities display evidence of an ICE and, if so, if this increase in sperm aneuploidy is comparable to that observed in men with similar semen parameters but who are chromosomally normal. Sperm aneuploidy was analysed from 9 proven fertile men, 10 chromosomally normal men with severe OAT and 8 carriers of structural chromosomal abnormalities with severe types of abnormal sperm parameters, including 5 translocations, 2 inversions and a complex chromosomal rearrangement.
We observed significant inter-individual variation in disomy rates within the control group, which is consistent with other reports on normal men (Rubes et al., 2005). This variation in sperm aneuploidy may be related to the variation in the frequency of meiotic recombination that has been reported among normal men (Lynn et al., 2002; Sun et al., 2005; Ferguson, et al., 2007). Inter-individual variation in disomy rates was observed for all chromosomes studied in the OAT group, as well as the group of chromosomal rearrangement carriers. Aneuploidy for the sex chromosomes was most frequently increased in the OAT men, suggesting that the sex chromosomes may have an increased susceptibility for segregation error in spermatogenesis, or that sperm maturation is more tolerant of errors in segregation involving sex chromosomes compared with that of the autosomes. Several other studies have found that patients with <5 x 106/ml sperm concentrations have particularly higher rates chromosomal abnormalities in their sperm (Vegetti et al., 2000; Calogero et al., 2001; Rubio et al., 2001; Martin et al., 2003). While seven of the men with severe OAT in our study showed a significant increase in XY disomy, considerable heterogeneity existed between individuals, with the level of increased sex chromosome aneuploidy ranging from slight to extreme (i.e. up to a 100-fold increase compared with the controls). In contrast, none of the carriers of structural abnormalities showed a significant increase in XY disomy when compared with the control group. Thus, it appears that infertile carriers of structural chromosomal abnormalities may produce lower magnitudes of sperm aneuploidy than chromosomally normal men with similarly impaired semen parameters.
Several recent meiotic studies on infertile 46,XY men have shown that a subset of this population display defective recombination, as well as abnormalities in the pairing of meiotic chromosomes (Gonsalves et al., 2004; Sun et al., 2007). In the present study, we found that the chromosomally normal men with OAT produced elevated rates of sperm aneuploidy, which may be related to defects in meiotic recombination. In a previous study, we analysed meiotic recombination and sperm aneuploidy in infertile men with either severe OAT or non-obstructive azoospermia and found that a subset of these men displayed defective recombination, particularly involving the sex chromosomes (Ferguson et al., 2007). Furthermore, a high frequency of sex chromosomes lacking recombination was found to increase the risk of sex chromosome aneuploidy in the sperm. Thus, the elevated sex chromosomes aneuploidy that we observed in the sperm of our chromosomally normal OAT population may be the result of defective sex chromosome recombination during meiosis in these men.
Although recombination defects may contribute to infertility and the increased incidence of sperm aneuploidy in some chromosomally normal men, this mechanism does not appear to be a major factor in carriers of chromosomal rearrangements. Recent meiotic studies on translocation carriers have suggested that, although recombination may be disturbed specifically on the rearranged chromosomes, recombination on other chromosomes appears to be unaffected (Oliver-Bonet et al., 2005; Pigozzi et al., 2005; Ferguson et al., 2008). Thus, the differences in sperm aneuploidy rates between infertile men with normal karyotypes and carriers of structural abnormalities is most likely due to mechanistic differences in both the cause of infertility, and the cause of meiotic non-disjunction. Meiotic studies on infertile carriers of translocations have shown that the fidelity of synapsis is often compromised in the rearranged chromosomes (Chandley et al., 1986; Gabriel-Robez et al., 1986; Oliver-Bonet et al., 2005). These asynapsed regions of the translocation are transcriptionally silenced, leading to meiotic arrest and infertility in the carrier (Turner et al., 2005). However, these asynapsed regions have also been found to associate with the sex chromosomes during meiosis, and it has been suggested that this interaction may interfere with the disjunction of the sex chromosomes, as well as other autosomal chromosomes (Anton et al., 2004). This translocation-XY association may explain the increased incidence of XY sperm disomy observed in other studies on carriers of chromosomal rearrangements (Anton et al., 2004, Douet-Guilbert et al.; 2005, Machev et al.; 2005). Interestingly, we did not observe a significant increase in sex chromosome aneuploidy in our carriers of chromosomal rearrangements, which may suggest a low frequency of translocation-XY associations in these men. Meiotic studies on infertile carriers of translocation have shown that the frequency of translocation-XY associations can vary widely between different rearrangements (Oliver-Bonet et al. 2005, Pigozzi et al. 2005, Ferguson et al., 2008), which may explain the variability in sex chromosome aneuploidy among translocation carriers. Nevertheless, there is relatively little information on the pairing and recombination of meiotic chromosomes in carriers of rearrangements, and the hypothesized mechanisms for the origin of an ICE are largely speculative.
It has been suggested that the presence of an ICE in infertile carriers of chromosomal rearrangements may simply be related to the impaired semen parameters, which is known to be associated with elevated sperm aneuploidy. However, the results of this study suggest that meiotic non-disjunction is a more common occurrence in infertile men with a 46,XY karyotype than in those with abnormal karyotypes, despite their similar semen parameters. We observed evidence of an ICE in the three of the eight carriers of chromosomal rearrangements. The magnitude of increased aneuploidy in the carriers of chromosomal rearrangements was smaller than that observed in the chromosomally normal men with severe OAT, and none of the carriers of chromosomal rearrangements showed an increase in sex chromosome aneuploidy. The difference in the magnitude and type of sperm aneuploidy between the two infertile groups is likely related to the different causes of infertility. Infertility in some 46,XY men with OAT may be related to defective meiotic recombination, leading to an increased risk of aneuploid sperm in these men (Ma et al., 2006, Ferguson et al., 2007). However, infertility in carriers of structural chromosomal abnormalities appears to be caused by asynapsis around the breakpoints, which may have only a minimal effect, if any, on the non-disjunction of chromosomes not involved in the rearrangement. Nevertheless, the existence or magnitude of an ICE may be dependent on the characteristics of the rearrangement, such as the chromosomes involved, sites of breakpoints and size of rearrangement. Thus, further studies are needed to determine if certain karyotypic abnormalities are most at risk of an ICE, and detailed meiotic studies on carriers of chromosomal rearrangements will be necessary in order to shed light on the mechanisms that may contribute to an ICE.
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This work was supported by funds from the Canadian Institutes of Health Research (MOP53067 to S.M.). K.A.F is the recipient of the Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada, and the Junior Graduate Studentship from the Michael Smith Foundation for Health Research.
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We gratefully thank the patients for donating samples, as well as Dr Timothy Rowe and the UBC Division of Reproductive Endocrinology and Infertility in the Department of Obstetrics and Gynaecology at the University of British Columbia for their support in this study.
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These authors contributed equally to this work. 
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Submitted on December 10, 2007; resubmitted on January 28, 2008; accepted on March 21, 2008.
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