Personalized and Precision Medicine Journal
Where Innovations Meets Personalized and Precision Medicine

Association Between Semen Paraoxonase-1 Activity Level and L55M Gene Variants with Risk of Male Infertility

Document Type : Original Article

Authors

Hanie Mortezapour 1
Abasalt Hosseinzadeh Colagar 2
Fatemeh Fallah 1
Ali Taravati 3
Seyed Gholam Ali Jorsaraei 4

1 Department of Molecular and Cell Biology, Faculty of Science, University of Mazandaran, Babolsar, CP:47416-95447, Mazandaran, Iran

2 Department of Molecular and Cell Biology, Faculty of Science, University of Mazandaran, CP:47416-95447, Mazandaran, Iran.

3 Department of Molecular and Cell Biology, Faculty of Science, University of Mazandaran, CP:47416-95447, Mazandaran, Iran

4 Department of Anatomy and Embryology, Infertility and Health Reproductive Research Center, Babol University of Medical Sciences, P.O. Box: 4136747176, Babol, Iran.

https://doi.org/10.22034/pmj.2025.2046951.1046
Abstract
Today evaluation of polymorphisms of the antioxidant enzyme-encoding genes, which affect the activity of antioxidant enzymes, could be used as risk prediction models for male infertility. This study aims to evaluate coloration of serum paraoxonase (PON1) activity levels in the semen and its L55M gene variants with risk male infertility. In a case-control study, semen samples were collected from 80 healthy controls and 128 infertile men at Fatemeh Al-Zahra IVF and Pastor Laboratory (Babol, Mazandaran, Iran). PON1 activity of semen samples was measured by spectrophotometric methods. Genotyping of all individuals based on PON1-L55M loci performed by PCR-RFLP and PCR-sequencing and molecular effects of leucine (L) to methionine (M) substitution were investigated by bioinformatics tools. Results showed a significant difference in genotype frequencies of PON1-L55M polymorphism between patient and control groups, and c.163T>A transition effect on the structure and function of PON1 protein. Also, TA genotype (OR=1.754, 95%CI=0.971 to 3.166, P= 0.062) and AA genotype (OR=5.067, 95%CI=1.366 to 18.789, P= 0.015) were associated with male infertility. Men with mutant allele (AA+TA) are exposed to be at the risk of male infertility (OR= 1.990, 95%CI= 1.118 to 3.54, P= 0.019). Also, the allelic analysis showed that the A allele was associated with the increased risk of idiopathic male infertility (OR= 1.749, 95%CI= 1.143 to 2.676, P= 0.010). Additionally, PON1 activity was higher in the TT (LL) individuals compared to the TA (LM) and AA (MM) men in both groups (LL> LM> MM). Since, the PON1-L55M gene variants are related to PON1 activity levels in the semen and serum paraoxonase is known as an important antioxidant calcium-dependent enzyme, it could be implicated in male infertility. Based on these findings, the presence of mutant allele (A) and or decreasing semen’s PON1 level may be an indicator/ prediction factor for male infertility.

Keywords

Male infertility
Oxidative stress
PON1-L55M
Semen paraoxonase1

Subjects

1.Bisht S, Faiq M, Tolahunase M, et al. (2017). Oxidative stress and male infertility. Nat Rev Urol 14:470-85. 
2. Jarow JP, Sharlip ID, Belker AM, et al. (2002). Best practice policies for male infertility. Urol J 167: 2138-2144. 
3.HuynhT, Mollard R, Trounson A (2002). Selected genetic factors associated with male infertility. Hum Reprod Update 8:183-198. 
4. Mousavi-Nasab FS, Colagar AH (2018). Investigation of the association of endothelial nitric oxide synthase (eNOS)-T786C gene polymorphism with the risk of male infertility in an Iranian population. Environ Sci Pollut Res Int 27:22434-22440. 
5.Agarwal A, Prabakaran S, Allamaneni SS (2006). Relationship between oxidative stress, varicocele and infertility: a meta-analysis. Reprod Biomed Online 12:630-633. 
6.Capogrosso P, Ventimiglia E, Boeri L, et al. (2018). Male infertility as a proxy of the overall male health status. Minerva Urol Nefrol 70:286-299. 
7.Oberley TD (2002). Oxidative damage and cancer. Am J Pathol 160:403-408.
8.Aitken RJ, Buckingham DW, West KM (1992). Reactive oxygen species and human spermatozoa: analysis of the cellular mechanisms involved in luminol‐and lucigenin‐dependent chemiluminescence. J Cell Physiol 151:466-477. 
9.Wagner H, Cheng JW, Ko EY (2018). Role of reactive oxygen species in male infertility: An updated review of literature. Arab J Urol 16:35-43. 
10. Barati E, Nikzad H, Karimian M (2020). Oxidative stress and male infertility: Current knowledge of pathophysiology and role of antioxidant therapy in disease management. Cell Mol Life Sci 77:93-113. 
11.Aitken Rj, Krausz C (2001). Oxidative stress, DNA damage and the Y chromosome. Reproduction 122:497-506. 
12.Alahmar AT (2019). Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci 12: 4-18. 
13.Darbandi M, Darbandi S, Agarwal A, et al. (2018). Reactive oxygen species and male reproductive hormones. Reprod Biol Endocrinol B 16:1-4.  
14.Rossi G, Meazzi S, Giordano A, et al. (2020). Serum paraoxonase 1 activity in cats: analytical validation, reference intervals, and correlation with serum amyloid A and alpha-1-acid glycoprotein. J Vet Diagno Invest 32:844-855.
15. Meseguer M, Antonio Martinez-Conejero J, Muriel L, et al. (2007). The human sperm glutathione system: a key role in male fertility and successful cryopreservation. Drug Metab Lett 1:121-126. 
16. Sekhon L, Gupta S, Kim Y, et al. (2010). Female infertility and antioxidants. Curr Women’s Health Rev 6: 84-95. 
17.Tremellen K (2008). Oxidative stress and male infertility-a clinical perspective. Hum Reprod Update 14: 243-258. 
18.Barranco I, Tvarijonaviciute A, Perez‐Patiño C, et al. (2015). The activity of paraoxonase type 1 (PON‐1) in boar seminal plasma and its relationship with sperm quality, functionality, and in vivo fertility. Andrology 3:315-320. 
19.Motovali-Bashi M, Sedaghat S, Dehghanian F (2015). Association between serum paraoxonase 1 activities (PONase/AREase) and L55M polymorphism in risk of female infertility. Avicenna J Med Biotechnol 7:173-178.
20.Bahrehmand F, Vaisi-Raygani A, Rahimi Z, et al. (2014). Synergistic effects of BuChE non-UU phenotype and paraoxonase (PON1) 55 M allele on the risk of systemic lupus erythematosus: influence on lipid and lipoprotein metabolism and oxidative stress, preliminary report. Lupus 23:263-72. 
21.Ozer OF, Akbulut H, Guler EM, et al. (2019). Oxidative stress and phenotype frequencies of paraoxonase‐1 in teratozoospermia. Andrologia 51: e13299. 
22.Verit FF, Verit A, Ciftci H, et al. (2009). Paraoxonase‐1 activity in subfertile men and relationship to sperm parameters. J Androl 30:183-189. 
23.Précourt LP, Amre D, Denis MC, et al. (2011). The three-gene paraoxonase family: physiologic roles, actions and regulation. Atherosclerosis 214:20-36. 
24.Eom SY, Kim YS, Lee CJ, et al. (2011). Effects of intronic and exonic polymorphisms of paraoxonase 1 (PON1) gene on serum PON1 activity in a Korean population. J Korean Med Sci 26:720-725.
25.Marsillach J, Mackness B, Mackness M, et al. (2008). Immunohistochemical analysis of paraoxonases-1, 2, and 3 expressions in normal mouse tissues. Free Radic Biol Med 45:146-157. 
26.Lazaros LA, Xita NV, Hatzi EG, et al. (2011). Association of paraoxonase gene polymorphisms with sperm parameters. J Andrology 32:394-401. 
27.Primo-Parmo SL, Sorenson RC, Teiber J, et al. (1996). The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 33:498-507. 
28.Kim DS, Burt AA, Ranchalis JE, et al. (2011). Additional common polymorphisms in the PON gene cluster predict PON1 activity but not vascular disease. J Lipids 2012.
29.Fang DH, Fan CH, Ji Q, et al. (2012). Differential effects of paraoxonase 1 (PON1) polymorphisms on cancer risk: evidence from 25 published studies. Mol Biol Rep 39:6801-6809. 
30.Behrouzi S, Mashayekhi F, Bahadori MH (2018). The association of PON1 192 Q/R polymorphism with the risk of idiopathic male infertility in northern Iran. Avicenna J Med Biotechnol 10:253-256. 
31.Gupta N, Gill K, Singh S (2009). Paraoxonases: structure, gene polymorphism & role in coronary artery disease. Indian J Med Res 130:361-368. 
32.World Health Organisation (1999) WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. Cambridge University Press
33.MWer S, Dykes D, Polesky H (1998). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215. 
34.Green MR, Sambrook J (2012). Molecular cloning. A Laboratory Manual 4th. 
35.Benzie IF, Strain JJ (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239:70-76. 
36.Rao B, Soufir JC, Martin M, et al. (1998). Lipid peroxidation in human spermatozoa as relatd to midpiece abnormalities and motility. Gamete Res 24:127-134. 
37.Fallah F, Colagar AH, Saleh HA, et al. (2023). Variation of the Genes Encoding Antioxidant Enzymes SOD2 (rs4880), GPX1 (rs1050450) and CAT (rs1001179) and Susceptibility to Male Infertility: A Genetic Association Study and in silico Analysis. Environ Sci Pollut Res Int 30:86412-86424.  
38. Ayub A, Mackness MI, Arrol S, et al. (1999). Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol 19:330-335. 
39.Rajender S, Avery K, Agarwal A (2011). Epigenetics, spermatogenesis and male infertility. Mutat Res 727:62-71. 
40.Sansone A, Di Dato C, de Angelis C, et al. (2018). Smoke, alcohol and drug addiction and male fertility. Reprod Biol Endocrinol 16:1-11. 
41.Milnerowicz H, Kowalska K, Socha E (2015). Paraoxonase activity as a marker of exposure to xenobiotics in tobacco smoke. Int J Toxicol 34:224-232. 
42.Bizon A, Milnerowicz H (2018). The effect of divalent metal chelators and cadmium on serum phosphotriesterase, lactonase and arylesterase activities of paraoxonase 1. EnvironToxicol Pharmacol 58: 77-83. 
43.Akbar S, Wei Y, Yuan Y, et al. (2020). Gene expression profiling of reactive oxygen species (ROS) and antioxidant defense system following Sugarcane mosaic virus (SCMV) infection. BMC Plant Biol 20: 1-12. 
44.Levy D, Reichert CO, Bydlowski SP (2019). Paraoxonases activities and polymorphisms in elderly and old-age diseases: An overview. Antioxidants 8: 118.
45.Krausz C, Escamilla AR, Chianese C. (2015). Genetics of male infertility: from research to clinic. Reproduction 150: R159-R174. 
46.Chang J, Pan F, Tang Q, et al. (2017). eNOS gene T786C, G894T and 4a4b polymorphisms and male infertility susceptibility: a meta‐analysis. Andrologia 49: e12646. 
47.Kao YL, Donaghue K, Chan A, et al. (1998). A variant of paraoxonase (PON1) gene is associated with diabetic retinopathy in IDDM. J Clin Endocrinol Metab  83: 2589-2592. 
48.Luo JQ, Ren H, Liu MZ, et al. (2018). European versus Asian differences for the associations between paraoxonase‐1 genetic polymorphisms and susceptibility to type 2 diabetes mellitus. J Cell Mol Med 22:1720-1732. 
49.Tanhapour M, Miri A, Vaisi-Raygani A, et al. (2018). Synergism between apolipoprotein E Ɛ4 allele and paraoxonase (PON1) 55-M allele is associated with risk of systemic lupus erythematosus. Clin Rheumatol 37: 971-977. 
50.Alizadeh M, Nasiri M, Samadi M, et al. (1999). Association of M55L and Q192R polymorphisms of paraoxonase 1 gene (PON1) with recurrent pregnancy loss risk: A case–control study. Int J Reprod Biomed 19:559- 568.
Personalized and Precision Medicine Journal
Volume 10, Issue 36 - Serial Number 36
Original article
Winter 2025
Pages 19-28

  • Receive Date 11 November 2024
  • Revise Date 30 January 2025
  • Accept Date 26 February 2025

Home

Publication Ethics

Guide for Authors

Submit Manuscript

Contact Us