Skip to main content
PMC home page
Asian Journal of Andrology logoLink to Asian Journal of Andrology
. 2012 Jul 9;14(5):691–694. doi: 10.1038/aja.2012.39

Genetic variants in TP53 and MDM2 associated with male infertility in Chinese population

Cong Huang 1,2, Wei Liu 1,2, Gui-Xiang Ji 3, Ai-Hua Gu 1,2, Jian-Hua Qu 4, Ling Song 1,2, Xin-Ru Wang 1,2
PMCID: PMC3734978  PMID: 22773013

Abstract

The TP53, a transcriptional regulator and tumor suppressor, is functionally important in spermatogenesis. MDM2 is a key regulator of the p53 pathway and modulates p53 activity. Both proteins have been functionally linked to germ cell apoptosis, which may affect human infertility, but very little is known on how common polymorphisms in these genes may influence germ cell apoptosis and the risk of male infertility. Thus, this study was designed to test whether three previously described polymorphisms 72Arg>Pro (rs1042522) and the Ex2+19C>T (rs2287498) in TP53, and the 5′ untranslated region (5′ UTR) 309T>G (rs937283) in MDM2, are associated with idiopathic male infertility in a Chinese population. The three polymorphisms were genotyped using OpenArray assay in a hospital-based case–control study, including 580 infertile patients and 580 fertile controls. Our analyses revealed that TP53 Ex2+19C>T and MDM2 309T>G polymorphisms are associated with male infertility. Furthermore, we detected a nearly statistically significant additive interaction between TP53 rs2287498 and MDM2 rs937283 for the development of male infertility (Pinteraction=0.055). In summary, this study found preliminary evidence, demonstrating that genetic variants in genes of the TP53 pathway are risk factors for male infertility.

Keywords: apoptosis, male infertility, MDM2, polymorphisms, TP53

Introduction

Infertility is a worldwide health issue that affects almost 10%–15% of couples, among which about half of the cases are due to male factors.1,2 A couple is considered infertile when they have not conceived after a full year of regular sexual intercourse without contraception. Men are considered infertile if they produce no sperm cells (azoospermia), too few sperm cells (oligospermia), or if sperm cells are abnormal or die before they can reach the egg. However, the causes of most cases remain unknown.3 Semen quality is an important factor affecting male infertility. Germ cell apoptosis is a normal process during spermatogenesis. For example, the apoptotic Fas/Fasl pathway can mediate ordinary sperm production and affect semen parameters in human.4,5 Other studies have proved that TP53 and MDM2 may play an indispensable role in spermatogenesis.6 The spontaneous testicular germ cell apoptosis and germ cell quality control in spermatogenesis is TP53-mediated.7 It has been reported that TP53−/− mice exhibit significantly less mature motile spermatozoa than their TP53+/+ counterparts,8,9 and have testicular giant-cell degenerative syndrome. MDM2, which interacts with TP53 and inhibits TP53 cell-cycle arrest and apoptosis,10 is critical in regulating TP53 function. It is observed that MDM2 knockout mice is lethal in early embryogenesis, while mice with simultaneous knockout of TP53 and MDM2 can survive and develop normally, indicating that MDM2 is essential in negative regulation of TP53 during development.11 It is significant that both TP53 and MDM2 are haploinsufficient genes, with any change resulting in great impact on the function of the TP53 pathway.12,13 Although lots of single nucleotide polymorphisms (SNPs) affecting male infertility have been reported,2,14,15,16 few researchers have thought about SNPs in the apoptosis pathway, especially TP53 and MDM2. Researchers have discovered numerous SNPs in the TP53 pathway, and some of them may alter the function of TP53 protein.17 For instance, a TP53 SNP in codon 72 results in a change from Arginine (Arg) to Proline (Pro).13 It has also been reported that MDM2 SNP309 can increase MDM2 expression and leads to attenuation of TP53 function.18

Although polymorphisms of TP53 and MDM2 have an impact on sperm apoptotic mechanism to some degree, no study has clarified whether their polymorphisms are associated with the risk of infertility in Chinese man. In this study, we compared the genotypes of three polymorphisms between infertile men and health controls to explore the risk factor of male infertility for the first time.

Materials and methods

Subjects

A total of 580 infertile men were recruited from the Centre of Clinical Reproductive Medicine between April 2004 and May 2007. All of the patients received physical tests, semen analyses, serum determination of follicle-stimulating hormone, luteinizing hormone and testosterone, karyotyping, and Y-chromosome microdeletion screening. The inclusion criteria consisted of six terms: (i) azoospermia or severe oligozoospermia (sperm count <5×106 ml−1) as demonstrated by at least two semen analyses performed according to the World Health Organization criteria (World Health Organization report, 1999); (ii) a normal 46 karyotype with XY sex chromosome; (iii) absence of Y chromosomal microdeletions of AZF region proved by the corresponding molecular analysis;19 (iv) lack of hypogonadotropic hypogonadism; (v) normal sexual and ejaculatory functions and no seminal tract obstruction or varicocele; (vi) no history of infection or other diseases that could affect fertility. In total, 580 idiopathic infertile men aged from 25 to 38 years were eligible for this study. The control group consists of 580 fertile men who have fathered at least one child without assisted reproductive technologies and have normal semen quality. All the participants in our study are Chinese Han nationality. They all provided informed consent and completed a questionnaire which included information about personal background, cigarette smoking, drinking status, occupational and so on. Finally, 5 ml of peripheral blood was extracted for genomic DNA genotyping. The study was approved by the Ethics Review Board of Nanjing Medical University.

Genotyping

Genomic DNA was extracted from leucocyte pellet by proteinase K digestion and followed by phenol-chloroform extraction and ethanol precipitation. Genotyping was performed using the OpenArray platform (Applied Biosystems, Foster City, CA, USA), and a chip-based TaqMan genotyping technology was employed in the system. Genotyping was conducted and genotype data analysis were made by OpenArray SNP Genotyping Analysis Software V.1.0.3 (Applied Biosystems). For quality control, genotyping was done without knowledge of case/control status of subjects, and a random 5% of cases and controls were genotyped twice by different individuals, and the reproducibility was 100%. To confirm the genotyping results, selected PCR-amplified DNA samples (n=2, for each genotype) were examined by DNA sequencing and the results were also consistent.

Statistical analysis

The differences in genotype distributions of selected characteristics between cases and fertile controls were evaluated using chi-squared analysis. The association between polymorphisms and the risk of male infertility was estimated by comparing the odds ratios (OR) and their 95% confidence intervals (CI) with unconditional univariate and logistic regression models. The potential gene–gene interactions were evaluated by logistic regression analyses and tested by comparing the changes in deviance (−2 log likelihood) between models of main effects with or without the interaction term. All analyses were conducted in the Statistical Analysis System (version 9.13; SAS Institute, Cary, NC, USA), and the P<0.05 was used as the criterion of significance.

Results

The frequencies of distributions of the selected characteristics of age, smoking status, pack-years of smoking and drinking status in the study subjects are displayed in Table 1. We sought to investigate the effect of drinking status and cigarette smoking on fertility rate in a large, well-defined groups, in which the criteria define people who have ≥2 cigarette per day as ‘smokers' and people who drink ≥2 times per day as ‘drinkers'. No obvious differences were observed between cases and controls with regard to the drinking status and age (P>0.05). However, there was a significantly higher percentage of smokers among cases than controls (P=0.046). Among smokers, cases also reported greater cigarette consumption than controls, as assessed by the mean number of pack-years (P=0.019).

Table 1. Distribution of selected characteristics between cases and fertile controls.

Variables Controls (n=580) Cases (n=580) Pb
Age (mean±s.d.), year 28.1±3.2 28.2±3.3 0.600
Smoking status, n (%)      
 Never 306 (52.8) 272 (46.9) 0.046
 Ever 274 (47.2) 308 (53.1)  
Pack-years (mean±s.d.)a, year 4.1±4.3 4.7±4.4 0.019
Drinking status, n (%)      
 Never 504 (86.9) 500 (86.2) 0.731
 Ever 76 (13.1) 80 (13.8)  
Open in a new tab
a

Among ever smokers.

b

P values were derived from the chi-squared test for categorical variables (smoking and drinking status) and t-test for continuous variables (age and pack-years).

The frequencies of TP53 72Arg>Pro (rs1042522), Ex2+19C>T (rs2287498) and MDM2 309T>G (rs937283) genotypes in cases and controls and their associations with the risk of idiopathic male infertility are shown in Table 2. All observed SNPs were in Hardy–Weinberg equilibrium (P=0.181 for rs1042522, P=0.698 for rs2287498 and P=0.170 for rs937283, respectively). Overall, two SNPs (rs2287498 and rs937283) exhibited a significant association with the risk of male infertility under a dominant model (variant-containing genotypes vs. homozygous wild-type genotype). For the TP53 Ex2+19C>T (rs2287498) polymorphisms, carriers of variant allele (T allele) had a 46% increased risk of male infertility compared with individuals with common homozygous genotype (CC). Similarly, patients with the MDM2 rs937283 GG genotype exhibited a significantly increased male infertility risk (adjusted OR=1.55; 95% CI=1.11–2.16). However, as to the TP53 72Arg>Pro (rs1042522) polymorphisms, no significant differences were observed.

Table 2. Genotype and allele frequencies of TP53 and MDM2 genes among the patients and controls and their associations with male infertility.

Genotype Cases Controls Crude OR Adjusted OR P-valueb
  n (%) n (%) (95% CI) (95% CI)a Genotype Allele
TP53 72Arg>Pro (rs1042522)             0.361 0.146
 GG 154 (26.6) 170 (29.3) 1.00 1.00    
 GC 270 (46.6) 273 (47.1) 1.09 (0.83–1.44) 1.05 (0.79–1.38)    
 CC 156 (26.9) 137 (23.6) 1.26 (0.92–1.73) 1.20 (0.88–1.65)    
 GC+CC 426 (73.4) 410 (70.7) 1.15 (0.89–1.48) 1.10 (0.85–1.42)    
TP53 Ex2+19C>T (rs2287498)             0.0002 <0.001
 CC 239 (41.2) 296 (51.0) 1.00 1.00    
 CT 254 (43.8) 234 (40.3) 1.34 (1.05–1.72) 1.32 (1.03–1.69)    
 TT 87 (15.0) 50 (8.6) 2.15 (1.46–3.17) 2.11 (1.44–3.11)    
 CT+TT 341 (58.8) 284 (49.0) 1.49 (1.18–1.88) 1.46 (1.16–1.84)    
MDM2 5′ UTR T>G (rs937283)             0.011 0.004
 TT 120 (20.7) 149 (25.7) 1.00 1.00    
 TG 295 (50.9) 306 (52.8) 1.21 (0.90–1.61) 1.13 (0.85–1.51)    
 GG 165 (28.4) 125 (21.6) 1.65 (1.18–2.31) 1.55 (1.11–2.16)    
 TG+GG 460 (79.3) 431 (74.3) 1.31 (1.00–1.72) 1.23 (0.93–1.61)    
Open in a new tab

Abbreviations: 5′ UTR, 5′ untranslated region; CI, confidence interval; OR, odds ratio.

a

Adjusted for age, smoking and drinking status.

b

Two-sided chi-squared test for the distributions of genotype and allele frequencies.

P for Hardy-Weinberg (HW) equilibrium: rs1042522, P=0.181; rs2287498, P=0.698; rs937283, P=0.170.

We further evaluated the additive combined effects of the two high-risk genotypes on male infertility by combining the at-risk genotypes of TP53 rs2287498 and MDM2 rs937283. As shown in Table 3, 46.2% of the cases and 38.1% of the controls carried the four variant genotypes (TP53 rs2287498 CT/TT and MDM2 rs937283 TG/GG), and these carriers had an increased risk of male infertility (adjusted OR=1.95; 95% CI=1.32–2.90). Logistic regression analyses revealed nearly statistically significant additive interaction between TP53 rs2287498 and MDM2 rs937283 for the development of male infertility (P for additive interaction=0.055).

Table 3. Combined effect of TP53 Ex2+19C>T and MDM2 5′ UTR T>G on male infertility risk.

TP53 Ex2+19C>T (rs2287498) MDM2 5′ UTR T>G (rs937283) Cases, n (%) Controls, n (%) OR (95% CI)a
CC TT 47 (8.1) 86 (14.8) 1.00
CC TG/GG 192 (33.1) 210 (36.2) 1.57 (1.05–2.35)
CT/TT TT 73 (12.6) 63 (10.9) 1.99 (1.22–3.23)
CT/TT TG/GG 268 (46.2) 221 (38.1) 1.95 (1.32–2.90)
Pinteractionb       0.055
Open in a new tab

Abbreviations: 5′ UTR, 5′ untranslated region; CI, confidence interval; OR, odds ratio.

a

Odds ratio was adjusted for age, smoking and drinking status.

b

Pinteraction for additive interaction.

Discussion

In testis, apoptosis is a way to eliminate damaged germ cells during their development. The loss of functional p53 protein leads to a disruption in the apoptosis process. As essential genes in the apoptosis pathway, TP53 and MDM2 are thought to provide another level of stringency in addition to other spermatogenic ‘quality control' mechanisms. Moreover, TP53 contributes to the efficiency of DNA repair during the postmitotic stages of spermatogenesis.10 If either the TP53 or the MDM2 pathway is abnormal in its function, for example, some SNPs that affect their functions, infertility may occur.

It has been reported that TP53 72Arg>pro and MDM2 309T>G modify the activity or the levels of the TP53 protein, and polymorphisms of the two genes are associated with the risk of apoptosis disorder diseases, such as various cancers.20,21 The codon 72Arg allele induces apoptosis better than the codon 72Pro allele to the mitochondria.22 While considering that the 72Arg may enhance localization of the Arg72 variant to the mitochondria which participates in an important process of apoptosis, we also assumed that germ cell apoptosis may be affected by this pathway. Hence, we deemed that polymorphisms of TP53 and MDM2 may be associated with germ cell apoptosis and male infertility.

In this study, three functional polymorphisms (TP53 72Arg>Pro (rs1042522), TP53 5′ untranslated region (5′ UTR) Ex2+19C>T (rs2287498) and MDM2 5′ UTR 309T>G (rs937283)) in apoptosis pathway genes were genotyped for investigation of their roles in male fertility. To summarize, we found that the functional polymorphisms of TP53 Ex2+19C>T and MDM2 309T>G have a higher risk of male infertility. The results are consistent with previous data in cancer.23,24 Previous studies have shown that the GG type of MDM2 SNP309 is associated with an elevated expression of MDM2 protein.25 The elevated expression of MDM2 downregulates TP53 which leads to the inhibition of the TP53-induced apoptotic pathway. Although our results suggest that the SNP of TP53 72Arg>Pro does not directly cause idiopathic male infertility, they may perhaps affect male fertility by combining with some additional polymorphisms in other genes or do not have inherited risk factors.

Another interesting finding in our study was that smoking status has a negative effect on reproduction (P<0.05). To date, cigarette consumption is a worldwide health problem. However, studies investigating the relationship between smoking and infertility have provided some inconsistent results. A population study of Jordanians found that smokers had significantly lower sperm concentration and motility values and higher serum testosterone and luteinizing hormone levels than non-smokers.26 Another population study in Shandong, China, showed that the sperm density, viability and forward progression, and the seminal plasma Zn, Cu and superoxide dismutase levels were negatively correlated with the amount and duration of cigarette smoking (P<0.01).27 It is more likely that smoking is an extrinsic factor for sperm DNA damage, which is associated with a lower pregnancy rate and an increase of pregnancy loss in assisted reproduction treatments.28 Cigarette smoke contains a variety of reactive oxygen species, which would cause sperm DNA damage.29,30 Smoking may also damage the chromatin structure and produce endogenous DNA strand breaks in human sperm, resulting in a reduced semen quality.31 Levels of DNA damage tend to be higher in smokers.32 While in other population studies, for example, Gu et al.33 and Ji et al.34 found that tea consumption may affect sperm quality but not smoking, researchers have obtained different conclusions. This division may be explained by different study populations.

In addition to genotype changes affecting male reproductive health, we cannot ignore the importance of genotype–environment interactions. For examples, in Chinese workers, semen quality is affected by environment factor such as organophosphate pesticide exposure, and genetic factor such as polymorphisms in the paraoxonase gene, which is involved in the metabolism of these pesticides.35 An additional example of gene–environment interaction is the C677T polymorphism in the gene encoding for methylenetetrahydrofolate reductase, and it showed that the positive effect of folic acid and zinc sulphate supplementation on sperm concentration was seen only in subjects without the T variant (CC homozygotes). However, in the present study, the polymorphism itself was not a risk factor for male subfertility.36

In summary, our study showed for the first time that TP53 Ex2+19C>T and MDM2 309T>G polymorphisms are associated with male infertility, based on a Chinese population including 580 infertile men and 580 health controls. We will explore genotype–environment interactions on Chinese male infertility in the future. A larger sample size is needed to confirm our results, and in vivo functional studies are also necessary to identify the biological mechanisms.

Author contributions

CH was the main investigator, wrote the article and participated in the conception of the study. GXJ performed the acquisition, analysis of data and the patient recruitment, follow-up and drafting of the article. WL and JHQ participated in the execution of the study. AHG made important contributions to the study design and sample collection. LS assisted in performing the experiment. XRW designed the study and is the corresponding author of the article. All authors read and approved the final manuscript.

Acknowledgments

We thank Yong Zhou (Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA) for language editing. This study was supported by grants of The Key Project of National Natural Science Foundation of China (No. 30930079) and National Natural Science Foundation of China (No. 81172696).

The authors confirm that there is no conflict of interest.

References

  1. de Kretser DM. Male infertility. Lancet. 1997;349:787–90. doi: 10.1016/s0140-6736(96)08341-9. [DOI] [PubMed] [Google Scholar]
  2. Gu A, Ji G, Long Y, Zhou Y, Shi X, et al. Assessment of an association between an aryl hydrocarbon receptor gene (AHR) polymorphism and risk of male infertility. Toxicol Sci. 2011;122:415–21. doi: 10.1093/toxsci/kfr137. [DOI] [PubMed] [Google Scholar]
  3. Filipponi D, Feil R. Perturbation of genomic imprinting in oligozoospermia. Epigenetics. 2009;4:27–30. doi: 10.4161/epi.4.1.7311. [DOI] [PubMed] [Google Scholar]
  4. Lee J, Richburg JH, Younkin SC, Boekelheide K. The Fas system is a key regulator of germ cell apoptosis in the testis. Endocrinology. 1997;138:2081–8. doi: 10.1210/endo.138.5.5110. [DOI] [PubMed] [Google Scholar]
  5. Sakkas D, Mariethoz E, St John JC. Abnormal sperm parameters in humans are indicative of an abortive apoptotic mechanism linked to the Fas-mediated pathway. Exp Cell Res. 1999;251:350–5. doi: 10.1006/excr.1999.4586. [DOI] [PubMed] [Google Scholar]
  6. Beumer TL, Roepers-Gajadien HL, Gademan IS, van Buul PP, Gil-Gomez G, et al. The role of the tumor suppressor p53 in spermatogenesis. Cell Death Differ. 1998;5:669–77. doi: 10.1038/sj.cdd.4400396. [DOI] [PubMed] [Google Scholar]
  7. Yin Y, Stahl BC, DeWolf WC, Morgentaler A. p53-mediated germ cell quality control in spermatogenesis. Dev Biol. 1998;204:165–71. doi: 10.1006/dbio.1998.9074. [DOI] [PubMed] [Google Scholar]
  8. Rotter V, Schwartz D, Almon E, Goldfinger N, Kapon A, et al. Mice with reduced levels of p53 protein exhibit the testicular giant-cell degenerative syndrome. Proc Natl Acad Sci USA. 1993;90:9075–9. doi: 10.1073/pnas.90.19.9075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Schwartz D, Goldfinger N, Kam Z, Rotter V. p53 controls low DNA damage-dependent premeiotic checkpoint and facilitates DNA repair during spermatogenesis. Cell Growth Differ. 1999;10:665–75. [PubMed] [Google Scholar]
  10. Kubbutat MH, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2. Nature. 1997;387:299–303. doi: 10.1038/387299a0. [DOI] [PubMed] [Google Scholar]
  11. Jones SN, Roe AE, Donehower LA, Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995;378:206–8. doi: 10.1038/378206a0. [DOI] [PubMed] [Google Scholar]
  12. Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored. Cell Death Differ. 2006;13:1027–36. doi: 10.1038/sj.cdd.4401910. [DOI] [PubMed] [Google Scholar]
  13. Hu W, Feng Z, Levine AJ. The regulation of human reproduction by p53 and its pathway. Cell Cycle. 2009;8:3621–2. doi: 10.4161/cc.8.22.9938. [DOI] [PubMed] [Google Scholar]
  14. A ZC, Yang Y, Zhang SZ, Li N, Zhang W. Single nucleotide polymorphism C677T in the methylenetetrahydrofolate reductase gene might be a genetic risk factor for infertility for Chinese men with azoospermia or severe oligozoospermia. Asian J Androl. 2007;9:57–62. doi: 10.1111/j.1745-7262.2007.00225.x. [DOI] [PubMed] [Google Scholar]
  15. Wu Q, Chen GW, Yan TF, Wang H, Liu YL, et al. Prevalent false positives of azoospermia factor a (AZFa) microdeletions caused by single-nucleotide polymorphism rs72609647 in the sY84 screening of male infertility. Asian J Androl. 2011;13:877–80. doi: 10.1038/aja.2011.51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Lazaros L, Xita N, Hatzi E, Kaponis A, Makrydimas G, et al. Phosphatidylethanolamine N-methyltransferase and choline dehydrogenase gene polymorphisms are associated with human sperm concentration Asian J Androle-pub ahead of print 5 March 2012 doi: 10.1038/aja.2011.125. [DOI] [PMC free article] [PubMed]
  17. Hu W, Feng Z, Atwal GS, Levine AJ. p53: a new player in reproduction. Cell Cycle. 2008;7:848–52. doi: 10.4161/cc.7.7.5658. [DOI] [PubMed] [Google Scholar]
  18. Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591–602. doi: 10.1016/j.cell.2004.11.022. [DOI] [PubMed] [Google Scholar]
  19. Wu B, Lu NX, Xia YK, Gu AH, Lu CC, et al. A frequent Y chromosome b2/b3 subdeletion shows strong association with male infertility in Han-Chinese population. Hum Reprod. 2007;22:1107–13. doi: 10.1093/humrep/del499. [DOI] [PubMed] [Google Scholar]
  20. Boersma BJ, Howe TM, Goodman JE, Yfantis HG, Lee DH, et al. Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst. 2006;98:911–9. doi: 10.1093/jnci/djj245. [DOI] [PubMed] [Google Scholar]
  21. Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, et al. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet. 2006;43:531–3. doi: 10.1136/jmg.2005.037952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Dumont P, Leu JI, Della PA, George DL, Murphy M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet. 2003;33:357–65. doi: 10.1038/ng1093. [DOI] [PubMed] [Google Scholar]
  23. Okishiro M, Kim SJ, Tsunashima R, Nakayama T, Shimazu K, et al. MDM2 SNP309 and TP53 R72P associated with severe and febrile neutropenia in breast cancer patients treated with 5-FU/epirubicin/cyclophosphamide. Breast Cancer Res Treat. 2011;132:947–53. doi: 10.1007/s10549-011-1637-5. [DOI] [PubMed] [Google Scholar]
  24. Zhao E, Cui D, Yuan L, Lu W. MDM2 SNP309 polymorphism and breast cancer risk: a meta-analysis. Mol Biol Rep. 2011;39:3471–7. doi: 10.1007/s11033-011-1119-1. [DOI] [PubMed] [Google Scholar]
  25. Nayak MS, Yang JM, Hait WN. Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs. Cancer Res. 2007;67:5831–9. doi: 10.1158/0008-5472.CAN-06-4533. [DOI] [PubMed] [Google Scholar]
  26. Al-Matubsi HY, Kanaan RA, Hamdan F, Salim M, Oriquat GA, et al. Smoking practices in Jordanian people and their impact on semen quality and hormonal levels among adult men. Cent Eur J Public Health. 2011;19:54–9. doi: 10.21101/cejph.a3629. [DOI] [PubMed] [Google Scholar]
  27. Zhang JP, Meng QY, Wang Q, Zhang LJ, Mao YL, et al. Effect of smoking on semen quality of infertile men in Shandong, China. Asian J Androl. 2000;2:143–6. [PubMed] [Google Scholar]
  28. Koskimies AI, Savander M, Ann-Marie N, Kurunmaki H. Sperm DNA damage and male infertility. Duodecim. 2010;126:2837–42. Finnish. [PubMed] [Google Scholar]
  29. Wang X, Sharma RK, Sikka SC, Thomas AJ, Falcone T, et al. Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility. Fertil Steril. 2003;80:531–5. doi: 10.1016/s0015-0282(03)00756-8. [DOI] [PubMed] [Google Scholar]
  30. Agarwal A, Said TM. Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. Bju Int. 2005;95:503–7. doi: 10.1111/j.1464-410X.2005.05328.x. [DOI] [PubMed] [Google Scholar]
  31. Kunzle R, Mueller MD, Hanggi W, Birkhauser MH, Drescher H, et al. Semen quality of male smokers and nonsmokers in infertile couples. Fertil Steril. 2003;79:287–91. doi: 10.1016/s0015-0282(02)04664-2. [DOI] [PubMed] [Google Scholar]
  32. Potts RJ, Newbury CJ, Smith G, Notarianni LJ, Jefferies TM. Sperm chromatin damage associated with male smoking. Mutat Res. 1999;423:103–11. doi: 10.1016/s0027-5107(98)00242-5. [DOI] [PubMed] [Google Scholar]
  33. Gu AH, Ji GX, Zhou Y, Long Y, Shi XG, et al. Polymorphisms of nucleotide-excision repair genes may contribute to sperm DNA fragmentation and male infertility. Reprod Biomed Online. 2010;21:602–9. doi: 10.1016/j.rbmo.2010.06.025. [DOI] [PubMed] [Google Scholar]
  34. Ji G, Gu A, Hu F, Wang S, Liang J, et al. Polymorphisms in cell death pathway genes are associated with altered sperm apoptosis and poor semen quality. Hum Reprod. 2009;24:2439–46. doi: 10.1093/humrep/dep223. [DOI] [PubMed] [Google Scholar]
  35. Padungtod C, Niu T, Wang Z, Savitz DA, Christiani DC, et al. Paraoxonase polymorphism and its effect on male reproductive outcomes among Chinese pesticide factory workers. Am J Ind Med. 1999;36:379–87. doi: 10.1002/(sici)1097-0274(199909)36:3<379::aid-ajim5>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  36. Axelsson J, Bonde JP, Giwercman YL, Rylander L, Giwercman A. Gene–environment interaction and male reproductive function. Asian J Androl. 2010;12:298–307. doi: 10.1038/aja.2010.16. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Asian Journal of Andrology are provided here courtesy of Editorial Office of AJA.

RESOURCES