Effects of Streptozotocin Induced Diabetes on One-Carbon Cycle and Sperm Function

Document Type : Original Article

Authors

1 Department of Animal Biotechnology, Reproductive Biomedicine Research Center, Royan Institute for Biotechnology, Isfahan, Iran

2 Department of Physical Education and Sport Sciences, Faculty of Humanities, University of Kashan, Kashan, Iran

3 Parthenogen, R&D Department, Lugano, Switzerland

Abstract

Objective: Diabetic men suffer an increased risk of infertility associated with signs of oxidative damage and decreased
methylation in sperm pointing to a deficit of the one-carbon cycle (1CC). We aimed to investigate this deficit using mice
models (type 1 and 2) of streptozotocin-induced diabetes.
Materials and Methods: In this experimental study, 50 male mice, aged eight weeks, were divided randomly into
four groups: sham, control, type 1 diabetes mellitus (DM1), and DM2. The DM1 group was fed a normal diet (ND) for
eight weeks, followed by five consecutive days of intraperitoneal administration of Streptozotocin (STZ, 50 mg/kg body
weight). The DM2 group was fed a high-fat diet (HFD) for eight weeks, followed by a single intraperitoneal injection
of STZ (100 mg/kg). After twelve weeks, all the mice were euthanized, and study parameters assessed. In the sham
group, citrate buffer as an STZ solvent was injected.
Results: Both types of diabetic animals had serious impairment of spermatogenesis backed by increased DNA damage
(P=0.000) and decreased chromatin methylation (percent: P=0.019; intensity: P=0.001) and maturation (P=0.000).
The 1CC was deeply disturbed with increased homocysteine (P=0.000) and decreased availability of carbon units
[methionine (P=0.000), serine (P=0.088), folate (P=0.016), B12 (P=0.025)] to feed methylations.
Conclusion: We have observed a distinct impairment of 1CC within the testes of individuals with diabetes. We
speculate that this impairment may be linked to inadequate intracellular glucose and diminished carbon unit supply
associated with diabetes. As a result, interventions focusing on enhancing glucose uptake into sperm cells and providing
supplementary methyl donors have the potential to improve fertility issues in diabetic patients. However, additional
clinical testing is required to validate these hypotheses.

Keywords

Main Subjects

References

  1. Diabetes Canada Clinical Practice Guidelines Expert Committee; Punthakee Z, Goldenberg R, Katz P. Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndrome. Can J Diabetes. 2018; 42 Suppl 1: S10-S15.
  2. Caroppo E, Dattilo M. Sperm redox biology challenges the role of antioxidants as a treatment for male factor infertility. Fertil Steril Rev. 2022; 3(1): 90-104.
  3. Marengo B, Nitti M, Furfaro AL, Colla R, Ciucis CD, Marinari UM, et al. Redox homeostasis and cellular antioxidant systems: crucial players in cancer growth and therapy. Oxid Med Cell Longev. 2016; 2016: 6235641.
  4. Yan LJ. Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res. 2014; 2014: 137919.
  5. Yang H, Jin X, Kei Lam CW, Yan SK. Oxidative stress and diabetes mellitus. Clin Chem Lab Med. 2011; 49(11): 1773-1782.
  6. Fazakerley DJ, Krycer JR, Kearney AL, Hocking SL, James DE. Muscle and adipose tissue insulin resistance: malady without mechanism? J Lipid Res. 2019; 60(10): 1720-1732.
  7. Sahakyan G, Vejux A, Sahakyan N. The role of oxidative stressmediated inflammation in the development of T2DM-induced diabetic nephropathy: possible preventive action of tannins and other oligomeric polyphenols. Molecules. 2022; 27(24): 9035.
  8. Rubini E, Baijens IMM, Horánszky A, Schoenmakers S, Sinclair KD, Zana M, et al. Maternal one-carbon metabolism during the periconceptional period and human foetal brain growth: a systematic review. Genes (Basel). 2021; 12(10): 1634.
  9. Clare CE, Brassington AH, Kwong WY, Sinclair KD. One-carbon metabolism: linking nutritional biochemistry to epigenetic programming of long-term development. Annu Rev Anim Biosci. 2019; 7: 263-287.
  10. Tiwari BK, Pandey KB, Abidi AB, Rizvi SI. Markers of oxidative stress during diabetes mellitus. J Biomark. 2013; 2013: 378790.
  11. Ereño-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martínez-Cruz LA. Structural insight into the molecular mechanism of allosteric activation of human cystathionine β-synthase by S-adenosylmethionine. Proc Natl Acad Sci USA. 2014; 111(37): E3845-E3852.
  12. Menezo YJ, Silvestris E, Dale B, Elder K. Oxidative stress and alterations in DNA methylation: two sides of the same coin in reproduction. Reprod Biomed Online. 2016; 33(6): 668-683.
  13. Bahreinian M, Tavalaee M, Abbasi H, Kiani-Esfahani A, Shiravi AH, Nasr-Esfahani MH. DNA hypomethylation predisposes sperm to DNA damage in individuals with varicocele. Syst Biol Reprod Med. 2015; 61(4): 179-186.
  14. Tunc O, Tremellen K. Oxidative DNA damage impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet. 2009; 26(9-10): 537-544.
  15. Dattilo M, D’Amato G, Caroppo E, Ménézo Y. Improvement of gamete quality by stimulating and feeding the endogenous antioxidant system: mechanisms, clinical results, insights on gene-environment interactions and the role of diet. J Assist Reprod Genet. 2016; 33(12): 1633-1648.
  16. Ding GL, Liu Y, Liu ME, Pan JX, Guo MX, Sheng JZ, et al. The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. Asian J Androl. 2015; 17(6): 948-953.
  17. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. J Pharmacol Pharmacother. 2010; 1(2): 94-99.
  18. Lin CC, Huang WJ, Chen KK. Measurement of testicular volume in smaller testes: how accurate is the conventional orchidometer? J Androl. 2009; 30(6): 685-689.
  19. Zhang LT, Kim HK, Choi BR, Zhao C, Lee SW, Jang KY, et al. Analysis of testicular-internal spermatic vein variation and the recreation of varicocoele in a Sprague-Dawley rat model. Andrology. 2014; 2(3): 466-473.
  20. Tonne JM, Sakuma T, Munoz-Gomez M, El Khatib M, Barry MA, Kudva YC, et al. Beta cell regeneration after single-round immunological destruction in a mouse model. Diabetologia. 2015; 58(2): 313-323.
  21. Pouriayevali F, Tavalaee M, Taktaz-Hafshejani T, Dattilio M, Nasr- Esfahani MH. Overlapping sperm damages from vitamin B or D deficiency in mice: Insights into the role of clinical supplementations. Andrologia. 2022; 54(11): e14592.
  22. Amaral S, Oliveira PJ, Ramalho-Santos J. Diabetes and the impairment of reproductive function: possible role of mitochondria and reactive oxygen species. Curr Diabetes Rev. 2008; 4(1): 46-54.
  23. Andlib N, Sajad M, Kumar R, Thakur SC. Abnormalities in sex hormones and sexual dysfunction in males with diabetes mellitus: A mechanistic insight. Acta Histochem. 2023; 125(1): 151974.
  24. Dimakopoulou A, Jayasena CN, Radia UK, Algefari M, Minhas S, Oliver N, et al. Animal models of diabetes-related male hypogonadism. Front Endocrinol (Lausanne). 2019; 10: 628.
  25. Chen M, Zheng H, Xu M, Zhao L, Zhang Q, Song J, et al. Changes in hepatic metabolic profile during the evolution of STZ-induced diabetic rats via an 1H NMR-based metabonomic investigation. Biosci Rep. 2019; 39(4): BSR20181379.
  26. Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res. 2001; 50(6): 537-546.
  27. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med. 2013; 34(2-3): 121-138.
  28. Jacobs RL, House JD, Brosnan ME, Brosnan JT. Effects of streptozotocin- induced diabetes and of insulin treatment on homocysteine metabolism in the rat. Diabetes. 1998; 47(12): 1967-1970.
  29. Portela JM, Tavares RS, Mota PC, Ramalho-Santos J, Amaral S.High glucose concentrations per se do not adversely affect humansperm function in vitro. Reproduction. 2015; 150(1): 77-84.
  30. Williams AC, Ford WC. The role of glucose in supporting motility and capacitation in human spermatozoa. J Androl. 2001; 22(4): 680-695.
  31. Sowers ML, Herring J, Zhang W, Tang H, Ou Y, Gu W, et al. Analysis of glucose-derived amino acids involved in one-carbon and cancer metabolism by stable-isotope tracing gas chromatography mass spectrometry. Anal Biochem. 2019; 566: 1-9.
  32. Bao J, Bedford MT. Epigenetic regulation of the histone-to-protamine transition during spermiogenesis. Reproduction. 2016; 151(5): R55-R70.
  33. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009; 9(6): 565-566.
  34. Vangipurapu J, Stancáková A, Smith U, Kuusisto J, Laakso M. Nine amino acids are associated with decreased insulin secretion and elevated glucose levels in a 7.4-year follow-up study of 5,181 finnish men. Diabetes. 2019; 68(6): 1353-1358.
  35. Barrea L, Vetrani C, Verde L, Frias-Toral E, Ceriani F, Cernea S, et al. Comprehensive approach to medical nutrition therapy in patients with type 2 diabetes mellitus: from diet to bioactive compounds. Antioxidants (Basel). 2023; 12(4): 904.
  36. Wensink MJ, Lu Y, Tian L, Shaw GM, Rizzi S, Jensen TK, et al. preconception antidiabetic drugs in men and birth defects in offspring: a nationwide cohort study. Ann Intern Med. 2022; 175(5): 665-673.

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