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Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

This study was conducted in order to investigate the effects of reactive oxygen species (ROS) levels on the seminal plasma (SP) metabolite milieu and sperm dysfunction.

Methods

Semen specimens of 151 normozoospermic men were analyzed for ROS by chemiluminescence and classified according to seminal ROS levels [in relative light units (RLU)/s/106 sperm]: group 1 (n = 39): low (ROS < 20), group 2 (n = 38): mild (20 ≤ ROS < 40), group 3 (n = 31): moderate (40 ≤ ROS < 60), and group 4 (n = 43): high (ROS ≥ 60). A comprehensive analysis of SP and semen parameters, including conventional semen characteristics, measurement of total antioxidant capacity (TAC), sperm DNA fragmentation index (DFI), chromatin maturation index (CMI), H19-Igf2 methylation status, and untargeted seminal metabolic profiling using nuclear magnetic resonance spectroscopy (1H-NMR), was carried out.

Result(s)

The methylation status of H19 and Igf2 was significantly different in specimens with high ROS (P < 0.005). Metabolic fingerprinting of these SP samples showed upregulation of trimethylamine N-oxide (P < 0.001) and downregulations of tryptophan (P < 0.05) and tyrosine/tyrosol (P < 0.01). High ROS significantly reduced total sperm motility (P < 0.05), sperm concentration (P < 0.001), and seminal TAC (P < 0.001) but increased CMI and DFI (P < 0.005). ROS levels have a positive correlation with Igf2 methylation (r = 0.19, P < 0.05), DFI (r = 0.40, P < 0.001), CMI (r = 0.39, P < 0.001), and trimethylamine N-oxide (r = 0.45, P < 0.05) and a negative correlation with H19 methylation (r = − 0.20, P < 0.05), tryptophan (r = − 0.45, P < 0.05), sperm motility (r = − 0.20, P < 0.05), sperm viability (r = − 0.23, P < 0.01), and sperm concentration (r = − 0.30, P < 0.001).

Conclusion(s)

Results showed significant correlation between ROS levels and H19-Igf2 gene methylation as well as semen parameters. These findings are critical to identify idiopathic male infertility and its management through assisted reproduction technology (ART).

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Acknowledgments

The authors would like to thank all patients and their family members who voluntarily participated in this study. In addition, we thank the director of the Phytochemistry and the Medicinal Chemistry Research Center at Shahid Beheshti University of Medicinal Sciences, SBMU (Iran, Tehran) and the Reproductive Center of Cleveland Clinic (Cleveland, USA) for their assistance.

Author’s roles

Mahsa Darbandi (data interpretation, study design, execution, analysis, manuscript drafting and revision), Sara Darbandi (data interpretation, study design, execution, analysis, manuscript drafting and revision), Ashok Agarwal (data interpretation, study design, analysis, manuscript review, revision and critical discussion), Saradha Baskaran (data interpretation, manuscript preparation, review and revision), Sulagna Dutta (data interpretation, manuscript preparation, review and revision), Pallav Sengupta (data interpretation, manuscript preparation, review and revision), Hamid Reza Khorram Khorshid (data interpretation, study design, manuscript drafting), Sandro Esteves (data interpretation, manuscript review and revision), Kambiz Gilany (acquisition of data, analysis), Mehdi Hedayati (data interpretation, study design, execution), Fatemeh Nobakht (acquisition of data, execution, analysis), Mohammad Mehdi Akhondi (data interpretation, study design), Niknam Lakpour (acquisition of data, study design, execution), and Mohammad Reza Sadeghi (data interpretation, study design, manuscript drafting and critical discussion). All authors read and approved the final manuscript.

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Authors and Affiliations

  1. Department of Embryology and Andrology, Reproductive Biotechnology Research Center, Avicenna Research Institute, ACECR, Tehran, 1936773493, Iran

    Mahsa Darbandi, Sara Darbandi, Kambiz Gilany & Niknam Lakpour

  2. American Center for Reproductive Medicine, Cleveland Clinic, Cleveland, OH, 44195, USA

    Ashok Agarwal & Saradha Baskaran

  3. Faculty of Dentistry, MAHSA University, 42610, Selangor, Malaysia

    Sulagna Dutta

  4. Department of Physiology, Faculty of Medicine, MAHSA University, 42610, Selangor, Malaysia

    Pallav Sengupta

  5. Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, 1985713834, Iran

    Hamid Reza Khorram Khorshid

  6. ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, 13075-460, Brazil

    Sandro Esteves

  7. Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University for Medical Sciences, Tehran, 1985717413, Iran

    Mehdi Hedayati

  8. Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Nishabur, 9314634814, Iran

    Fatemeh Nobakht

  9. Monoclonal Antibody Research Center, Avicenna Research Institute (ARI), ACECR, Shahid Beheshti University, Evin, Tehran, 1936773493, Iran

    Mohammad Mehdi Akhondi & Mohammad Reza Sadeghi

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  1. Mahsa Darbandi
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All applicable international, national, and/or institutional guidelines for the use of human tissues were followed. All procedures performed in studies involving human subjects were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Darbandi, M., Darbandi, S., Agarwal, A. et al. Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality. J Assist Reprod Genet 36, 241–253 (2019). https://doi.org/10.1007/s10815-018-1350-y

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