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Biol Reprod 2003, 10.1095/biolreprod.102.015149
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BIOLOGY OF REPRODUCTION 69, 535–539 (2003)
DOI: 10.1095/biolreprod.102.015149
© 2003 by the Society for the Study of Reproduction, Inc.

Gamete Biology

A Comparison of the Frequency of Sperm Chromosome Abnormalities in Men with Mild, Moderate, and Severe Oligozoospermia1

Renée H. Martin2,3,4, Alfred W. Rademaker5, Calvin Greene6, Evelyn Ko4, Tina Hoang4, Leona Barclay4, and Judy Chernos3,4

Department of Medical Genetics,3 University of Calgary, Calgary, Alberta, Canada T4N 4N1 Department of Genetics,4 Alberta Children's Hospital, Calgary, Alberta, Canada T2T 5C7 Cancer Center Biometry Section,5 Northwestern University Medical School, Chicago, Illinios 60611-4402 Department of Obstetrics and Gynecology,6 University of Calgary, Calgary, Alberta, Canada T4N 4N1


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Infertile men undergoing intracytoplasmic sperm injection have an increased frequency of chromosome abnormalities in their sperm. Men with low sperm concentration (oligozoospermia) have an increased risk of sperm chromosome abnormalities. This study was initiated to determine whether men with severe oligozoospermia (<106 sperm/ml) have a higher frequency of chromosome abnormalities in their sperm compared with men with moderate (1–9 x 106 sperm/ml) or mild (10–19 x 106 sperm/ml) oligozoospermia. Multicolor fluorescence in situ hybridization analysis was performed using DNA probes specific for chromosomes 13, 21, X, and Y (with chromosome 1 as an autosomal control for the sex chromosomes). Aneuploidy and disomy frequencies were assessed from a total of 603 011 sperm from 30 men: 10 in each of the categories. The mean frequencies of disomy for the patients with mild, moderate, and severe oligozoospermia were 0.17%, 0.24%, and 0.30%, respectively, for chromosome 13 and 0.22%, 0.44%, and 0.58%, respectively, for chromosome 21. For the sex chromosomes, the mean frequencies of disomy for mild, moderate, and severe oligozoospermia were 0.25%, 1.04%, and 0.68%, respectively, for XY, 0.047%, 0.08%, and 0.10%, respectively, for XX, and 0.04%, 0.06%, and 0.09%, respectively, for YY. The frequencies for diploidy also increased from 0.4% for mild to 1.20% for moderate to 1.24% for severe oligozoospermia. There was a significant inverse correlation between the frequency of sperm chromosome abnormalities and the sperm concentration for XY, XX, and YY disomy and diploidy. These results demonstrate that men with severe oligozoospermia have an elevated risk for chromosome abnormalities in their sperm, particularly sex chromosome abnormalities.

gamete biology, gametogenesis, meiosis, sperm, spermatogenesis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Infertility is caused by a male factor in approximately 50% of cases. Somatic chromosome abnormalities are associated with male infertility, particularly azoospermia and oligozoospermia [1, 2]. As expected, infertile men with a constitutional chromosome abnormality have an increased frequency of chromosomally unbalanced spermatozoa and offspring [3]. Infertile men with a normal 46,XY somatic karyotype also have an increased frequency of chromosomally abnormal sperm [4–10].

Men with an increased frequency of chromosome anomalies in sperm have produced chromosomally abnormal fetuses and children [11–15]. Results of pregnancies after intracytoplasmic sperm injection using sperm from infertile men have demonstrated an increased risk of de novo chromosome abnormalities in offspring [16, 17], the majority of which are paternally derived [18–20].

Infertile men may have abnormalities in one or many semen parameters, such as sperm concentration (oligozoospermia), motility (aesthenozoospermia), or morphology (teratozoospermia). It is very common to have abnormalities in all three major parameters (oligoaesthenoteratozoospermia). It has been hypothesized that oligozoospermia is the condition most strongly associated with an increased frequency of sperm chromosome abnormalities [5, 21]. If that were the case, men with more severe oligozoospermia would have a higher frequency of chromosome abnormalities in their sperm compared with men with moderate or mild oligozoospermia. To test this hypothesis, we studied aneuploidy for chromosomes 13, 21, X, and Y in sperm from 30 infertile men: 10 with mild oligozoospermia (10–19 x 106 sperm/ml), 10 with moderate oligozoospermia (1–9 x 106 sperm/ml), and 10 with severe oligozoospermia (<106 sperm/ml).


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Oligozoospermic patients were recruited from the University of Calgary Regional Fertility Program. Semen analyses were performed using WHO guidelines [22]. Patients were sorted into groups according to the degree of oligozoospermia: mild, moderate, or severe. There were varying degrees of aestheno- and teratozoospermia within these groups (Table 1). Patient ages ranged from 27 to 56 yr; mean ages within the mild, moderate, and severe oligozoospermia groups were 38.9, 37, and 37.8 yr, respectively, and overall mean age was 37.9 yr. All of the men had a normal 46,XY karyotype, and none had a history of radiotherapy, chemotherapy, chronic illness, or medication. Patients gave informed consent, and the institutional ethics board approved the research.


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  		TABLE 1. Patient ages and semen parameters

Probe Preparation

An X-specific {alpha}-satellite probe (kindly provided by E. Jabs, Johns Hopkins University, Baltimore, MD) [23] and a chromosome 1-specific satellite III sequence, pUC1.77 (generously provided by H.J. Cooke, Edinburgh, U.K.) [24] were labeled directly with Fluorogreen and Fluoroblue (Amersham, Baie d'Urfé, PQ, Canada), respectively, by nick translation. CEP SpectrumOrange Yq, LSI SpectrumGreen 13, and LSI SpectrumOrange 21 were purchased from Vysis (Downer's Grove, IL).

Semen Processing and Fluorescence In Situ Hybridization Analysis

Fresh semen specimens were collected in sterile containers and washed twice with 10 mM Tris, 0.9% NaCl, pH 8. For patients with extremely low quantities of sperm (those in the severe oligozoospermia group), up to four specimens were collected, with >=3 days between specimens. Each specimen was washed as above, and each patient's washed sperm samples were pooled before preparing slides. If the total sperm present in the patient's specimen was adequate, conventional fluorescence in situ hybridization analysis (FISH) was carried out [10]; otherwise microwave decondensation and codenaturation were used to conserve sperm on the slides [25]. The microwave technique does not alter the frequency of disomy or diploidy compared with the conventional processing technique [25].

Scoring of Sperm Nuclei

All slides were scored using an Axiophot or Axioplan epifluorescence microscope (Zeiss, Don Mills, ON, Canada) equipped with a fluorescein isothiocyanate (FITC)/rhodamine dual bandpass filter set, a 4',6'-diamidino-2-phenylindole (DAPI) single bandpass filter set, and an FITC/rhodamine/DAPI triple bandpass filter set. All scored cells had a clearly defined border and were not overlapping or decondensed to more than twice the size of undecondensed sperm. Sperm were scored as disomic when two same-color signals were clearly visible within the sperm, separated by the diameter of one signal (except overlarge Yq signals, which needed separation of half the diameter of the signal), and of similar intensity, size, and shape. The signal for chromosome 1 functioned only as an internal control to distinguish between disomy for the sex chromosomes (one chromosome 1 signal) and a diploid cell (two chromosome 1 signals).

Data Analysis

To analyze the effect of sperm concentration on the frequency of sperm chromosome abnormalities, a Spearman correlation was calculated for each individual chromosome. To investigate abnormalities across chromosomes within men, the total disomy and the total disomy plus diploid were also regressed against sperm concentration. Stepwise regression was used to determine which representation of abnormality frequencies (individual chromosomes, total disomy, total disomy plus diploid) was most highly correlated with sperm concentration.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Chromosome abnormalities were assessed for a minimum of 10 000 sperm per chromosome probe per donor for a total of 603 011 sperm. Achieving this minimum sample size was particularly difficult for the category of severe oligozoospermia (<106 sperm/ml). The individual disomy and diploidy frequencies for chromosomes 13, 21, X, and Y for patients with mild, moderate, and severe oligozoospermia are presented in Table 2. The mean frequencies for disomy 13 were 0.17% for patients with mild oligozoospermia, 0.24% for those with moderate oligozoospermia, and 0.3% for severe oligozoospermia. The frequencies for disomy 21 increased in a similar fashion with 0.22% for mild, 0.44% for moderate, and 0.58% for severe oligozoospermia. For the sex chromosomes, the mean frequencies of disomy for mild, moderate, and severe oligozoospermia, respectively, were 0.25%, 1.04%, and 0.68% for XY, 0.04%, 0.08%, and 0.10% for XX, and 0.04%, 0.06%, and 0.09% for YY. The frequencies for diploidy also increased from 0.4% for mild to 1.20% for moderate to 1.24% for severe oligozoospermia.


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  		TABLE 2. Individual sperm chromosome abnormality frequencies (%)

Analysis of the data using Spearman correlation of person-specific abnormality frequencies on the actual sperm concentration demonstrated that there was a marginal trend of increased chromosome abnormalities with decreased concentration for the autosomes (disomy 13: r = -0.30, P = 0.10; disomy 21: r = -0.31, P = 0.09) but a significant correlation for the sex chromosomes (XY: r = -0.47, P = 0.009; XX: r = -0.49, P = 0.006; YY: r = -0.40, P = 0.03) and diploid sperm (r = -0.47, P = 0.01). Across chromosomes, total abnormality frequencies were correlated with sperm concentration (total disomy: r = -0.56, P = 0.001; disomy plus diploid: r = -0.55, P = 0.002). Using stepwise regression, total disomy was the abnormality representation that was most highly correlated with sperm concentration, explaining 26% of the concentration variance (P = 0.003), with the XX abnormality frequency having the next highest correlation, explaining an additional 8% of the variance (P = 0.08). There were no significant Spearman correlations of age with any of the abnormalities.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We studied the frequencies of sperm chromosome abnormalities in autosomes and sex chromosomes in >600 000 sperm from infertile men with mild, moderate, or severe oligozoospermia. Frequencies of sperm chromosome abnormalities increased with decreased sperm concentration, particularly for the sex chromosomes and diploidy. Individual chromosome abnormality frequencies (Table 2) were significantly correlated with sperm concentration, also particularly for the sex chromosomes and diploidy. Total abnormality frequencies (Table 3) were the most significant correlate of sperm concentration, and once this variable was included in the model, no individual abnormality frequency was significant at P < 0.05. Thus, although individual chromosome abnormalities are significantly correlated with sperm concentration, the results of the individual analyses are not independent, and the aggregate abnormality frequency across chromosomes has a slightly better correlation with concentration.


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  		TABLE 3. Combined sperm chromosome abnormality frequencies (%)

The frequencies of sperm chromosome abnormalities were increased in men with moderate and severe oligozoospermia compared with normal control donors, but men with mild oligozoospermia were not significantly different from control donors [26, 27]. Thus, men with mild oligozoospermia have sperm abnormality frequencies that fall within the range of abnormalities found in normospermic men.

We also studied men with sperm motility problems (aesthenozoospermia with normal sperm concentration) [10] and abnormal sperm morphology (teratozoospermia with normal sperm concentration) [9]. In both of these studies, we found a modest but significant increase in the mean frequency of sperm chromosome abnormalities, approximately double that seen in control donors. The mean frequencies of abnormalities observed in men with oligozoospermia, particularly severe oligozoospermia, were more dramatic, with 3–4 times the mean frequencies of abnormalities observed in normal men [26, 27].

All of the chromosomes studied are clinically significant; triploidy or trisomies for all of these chromosomes can lead to pregnancy loss or the birth of children with mental and physical disabilities. When a sperm disomic for chromosome 13 or 21 fertilizes a normal oocyte, a conceptus with trisomy 13 (Patau syndrome) or 21 (Down syndrome) results. Although the majority of these embryos abort spontaneously, many progress to term. Down syndrome is the most common cause of mental retardation in humans. When XY, XX, or YY sperm fertilize normal oocytes, an embryo with XXY (Klinefelter syndrome), XXX, or XYY syndrome results. The majority of these embryos progress to term, and these individuals have variable problems with fertility, behavior, and learning and mental deficits.

Other researchers have also investigated the relationship between sperm concentration and chromosome abnormalities, although no other study has included as many men with sperm concentrations of <106 sperm/ml because it is extremely difficult to get adequate sample sizes for FISH analysis of 10 000 sperm/chromosome probe for these men. Rives et al. [28] studied 2 men with a sperm concentration of <106 sperm/ml, 24 with 1–9 x 106/ml, and 18 with 10–19 x 106/ml and found a significant correlation between sperm concentration and the mean frequency of disomy. This correlation was significant for both autosomes and sex chromosomes. Vegetti et al. [21] analyzed sperm concentration and total sperm chromosome abnormality frequency in 15 oligospermic men; one had a sperm concentration of <106 sperm/ml and 14 had 1–9 x 106 sperm/ml. The frequency of total sperm chromosome abnormalities was inversely correlated with the sperm concentration. Calogero et al. [29] studied 19 patients with oligoaesthenoteratozoospermia, one with <106 sperm/ml, 11 with 1–9 x 106 sperm/ml, and 3 with 10–19 x 106 sperm/ml. The pooled aneuploidy frequency for chromosomes 8, 12, 18, X, and Y was negatively correlated with sperm density. Ohashi et al. [30] studied chromosomes 18, X, and Y in 20 oligozoospermic men: 10 with sperm concentrations of <5 x 106 sperm/ml (1 man with <106 sperm/ml) and 10 with 5–20 x 106 sperm/ml. They found a significant increase in the frequency of XY disomy and diploidy for the group with severe oligozoospermia (<5 x 106 sperm/ml). Thus all of the study results are consistent, demonstrating a significant increase in the frequency of sperm chromosome abnormalities with decreasing sperm concentration, especially in severe oligozoospermia. Oligozoospermia and azoospermia have been associated with chromosome pairing abnormalities during meiosis. Egozcue et al. [31] reported that infertile males have an increased frequency of chromosome pairing disruptions resulting in meiotic arrest. A pairing abnormality in these infertile males could lead to meiotic arrest in some cells causing oligozoospermia and aneuploidy in other cells capable of completing spermatogenesis [5]. Both our study and that of Ohashi et al. [30] found that this inverse relationship between sperm concentration and abnormality frequency was particularly pronounced for the sex chromosomes. We [3, 32–35] and others [36–38] have previously observed that the sex chromosomes are particularly vulnerable to nondisjunction in both normal and infertile men. There is generally only one crossover between the X and Y chromosomes in the pseudoautosomal region, and if this structure is lost, normal disjunction is not assured. Hassold et al. [39] and Lorda Sanchez et al. [40] determined that there is a reduction in recombination for the XY bivalent in meiosis, leading to the 47,XXY karyotype (Klinefelter syndrome). We have used single-sperm polymerse chain reaction to demonstrate that reduced recombination in the pseudoautosomal region is associated with nondisjunction of the sex chromosomes [41]. Follow-up studies of babies born after intracytoplasmic sperm injection (with sperm from infertile men) have an increased frequency of de novo chromosome abnormalities, particularly for the sex chromosomes [16, 17].

This study of chromosome abnormalities in >600 000 sperm nuclei from 30 oligozoospermic men has revealed an inverse relationship between sperm concentration and chromosome abnormality frequency. Men with mild oligozoospermia fall within the reference range of normal control donors, but men with moderate and severe oligozoospermia have significantly increased frequencies of aneuploid and diploid sperm. Our study is the first to demonstrate definitively that men with severe oligozoospermia (<106 sperm/ml) have the highest frequency of sperm chromosome abnormalities and thus may have the greatest risk of producing a chromosomally abnormal child after undergoing intracytoplasmic sperm injection.


   ACKNOWLEDGMENTS
 
The authors gratefully acknowledge manuscript preparation by Linda Macaulay.


   FOOTNOTES
 
1 The research was supported by grant MA-7961 from the Canadian Institutes of Health Research. R.H.M. holds the Canada Research Chair in Genetics. Back

2 Correspondence: Renée H. Martin, Medical Genetics Clinic, 1820 Richmond Rd. SW, Calgary, AB, Canada T2T 5C7. FAX: 403 543 9100; rhmartin{at}ucalgary.ca Back

Received: 8 January 2003.

First decision: 31 January 2003.

Accepted: 8 April 2003.


   REFERENCES
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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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L. Rodrigo, C. Rubio, E. Mateu, C. Simon, J. Remohi, A. Pellicer, and M. Gil-Salom
Analysis of chromosomal abnormalities in testicular and epididymal spermatozoa from azoospermic ICSI patients by fluorescence in-situ hybridization
Hum. Reprod., January 1, 2004; 19(1): 118 - 123.
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