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Epigenetic modifications at DMRs of imprinting genes in sperm of type 2 diabetic men

Published online by Cambridge University Press:  23 May 2022

Maryam Jazayeri
Affiliation:
Department of Reproductive Biology, Faculty of Basic Sciences and Advanced Medical Technologies, Royan Institute, ACECR, Tehran, Iran Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, Iran
Poopak Eftekhari-Yazdi
Affiliation:
Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, Iran
Mohammad Ali Sadighi Gilani
Affiliation:
Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Mohsen Sharafi
Affiliation:
Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, Iran Department of Poultry Sciences, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
Abdolhossein Shahverdi*
Affiliation:
Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, Iran
*
Authors for correspondence: Abdolhossein Shahverdi. P.O. Box: 16635-148, Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran. E-mail: shahverdi@royaninstitute.org

Summary

High rates of infertility in type 2 diabetic (T2DM) men have led to attempts to understand the mechanisms involved in this process. This condition can be investigated from at least two aspects, namely sperm quality indices and epigenetic alterations. Epigenetics science encompasses the phenomena that can lead to inherited changes independently of the genetics. This study has been performed to test the hypothesis of the relationship between T2DM and the epigenetic profile of the sperm, as well as sperm quality indices. This research included 42 individuals referred to the infertility clinic of Royan Institute, Iran in 2019–2021. The study subjects were assigned to three groups: normozoospermic non-diabetic (control), normozoospermic diabetic (DN) and non-normozoospermic diabetic (D.Non-N). Sperm DNA fragmentation was evaluated using the sperm chromatin structure assay technique. The global methylation level was examined using 5-methyl cytosine antibody and the methylation status in differentially methylated regions of H19, MEST, and SNRPN was assessed using the methylation-sensitive high-resolution melting technique. The results showed that the sperm global methylation in spermatozoa of D.Non-N group was significantly reduced compared with the other two groups (P < 0.05). The MEST and H19 genes were hypomethylated in the spermatozoa of D.Non-N individuals, but the difference level was not significant for MEST. The SNRPN gene was significantly hypermethylated in these individuals (P < 0.05). The results of this study suggest that T2DM alters the methylation profile and epigenetic programming in spermatozoa of humans and that these methylation changes may ultimately influence the fertility status of men with diabetes.

Type
Research Article
Copyright
© Royan Institute for Reproductive Biomedicine, 2022. Published by Cambridge University Press

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References

Ali, S. T., Shaikh, R. N., Ashfaqsiddiqi, N. and Siddiqi, P. Q. (1993). Serum and urinary levels of pituitary-gonadal hormones in insulin-dependent and non-insulin-dependent diabetic males with and without neuropathy. Archives of Andrology, 30(2), 117123. doi: 10.3109/01485019308987744 CrossRefGoogle ScholarPubMed
Amaral, A., Lourenço, B., Marques, M. and Ramalho-Santos, J. (2013). Mitochondria functionality and sperm quality. Reproduction, 146(5), R163R174. doi: 10.1530/REP-13-0178 CrossRefGoogle ScholarPubMed
Åsenius, F., Danson, A. F. and Marzi, S. J. (2020). DNA methylation in human sperm: A systematic review. Human Reproduction Update, 26(6), 841873. doi: 10.1093/humupd/dmaa025 CrossRefGoogle ScholarPubMed
Assaad-Khalil, S. H. (2020). The diabetic foot worldwide: Middle East. The foot in diabetes: 7983.CrossRefGoogle Scholar
Bucci, D., Spinaci, M., Galeati, G. and Tamanini, C. (2020). Different approaches for assessing sperm function. Animal Reproduction, 16(1), 7280. doi: 10.21451/1984-3143-AR2018-122 CrossRefGoogle ScholarPubMed
Cole, J. B. and Florez, J. C. (2020). Genetics of diabetes mellitus and diabetes complications. Nature Reviews. Nephrology, 16(7), 377390. doi: 10.1038/s41581-020-0278-5 CrossRefGoogle ScholarPubMed
Cooper, T. G., Noonan, E., von Eckardstein, S., Auger, J., Baker, H. W., Behre, H. M., Haugen, T. B., Kruger, T., Wang, C., Mbizvo, M. T. and Vogelsong, K. M. (2010). World Health Organization reference values for human semen characteristics. Human Reproduction Update, 16(3), 231245. doi: 10.1093/humupd/dmp048 CrossRefGoogle ScholarPubMed
Daxinger, L. and Whitelaw, E. (2012). Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nature Reviews. Genetics, 13(3), 153162. doi: 10.1038/nrg3188 CrossRefGoogle ScholarPubMed
de Castro Barbosa, T., Ingerslev, L. R., Alm, P. S., Versteyhe, S., Massart, J., Rasmussen, M., Donkin, I., Sjögren, R., Mudry, J. M., Vetterli, L., Gupta, S., Krook, A., Zierath, J. R. and Barrès, R. (2016). High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Molecular Metabolism, 5(3), 184197. doi: 10.1016/j.molmet.2015.12.002 CrossRefGoogle ScholarPubMed
Desai, M., Jellyman, J. K. and Ross, M. G. (2015). Epigenomics, gestational programming and risk of metabolic syndrome. International Journal of Obesity, 39(4), 633641. doi: 10.1038/ijo.2015.13 CrossRefGoogle ScholarPubMed
Dias, B. G. and Ressler, K. J. (2014). Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neuroscience, 17(1), 8996. doi: 10.1038/nn.3594 CrossRefGoogle ScholarPubMed
Ding, G. L., Liu, Y., Liu, M. E., Pan, J. X., Guo, M. X., Sheng, J. Z. and Huang, H. F. (2015). The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis. Asian Journal of Andrology, 17(6), 948953. doi: 10.4103/1008-682X.150844 Google ScholarPubMed
Dong, H., Wang, Y., Zou, Z., Chen, L., Shen, C., Xu, S., Zhang, J., Zhao, F., Ge, S., Gao, Q., Hu, H., Song, M. and Wang, W. (2017). Abnormal methylation of imprinted genes and cigarette smoking: Assessment of their association with the risk of male infertility. Reproductive Sciences, 24(1), 114123. doi: 10.1177/1933719116650755 CrossRefGoogle ScholarPubMed
Fields, E., Chard, J., James, D., Treasure, T. and Development Group, Guideline. (2013). Fertility (update): Summary of NICE guidance. BMJ, 346, f650. doi: 10.1136/bmj.f650 CrossRefGoogle ScholarPubMed
Ghafouri-Fard, S., Esmaeili, M. and Taheri, M. (2020). H19 lncRNA: Roles in tumorigenesis. Biomedicine and Pharmacotherapy, 123, 109774. doi: 10.1016/j.biopha.2019.109774 CrossRefGoogle ScholarPubMed
Gosden, R., Trasler, J., Lucifero, D. and Faddy, M. (2003). Rare congenital disorders, imprinted genes, and assisted reproductive technology. Lancet, 361(9373), 19751977. doi: 10.1016/S0140-6736(03)13592-1 CrossRefGoogle ScholarPubMed
Habadi, M. I., Alrashidi, M. M., Mutaki, I. F., Alshammari, K. A., Alothayqi, J. H., Alenezi, A. F., Hethwell, S. A., Alruwaily, Y. M., Aloufi, Y. A. A., Almulla, T. R. and Al-Bogami, M. A. (2021). Diagnosis of dysglycemia in diabetic patients in primary health care. Journal of Pharmaceutical Research International, 1419. doi: 10.9734/jpri/2021/v33i30A31609 CrossRefGoogle Scholar
Hammoud, S. S., Purwar, J., Pflueger, C., Cairns, B. R. and Carrell, D. T. (2010). Alterations in sperm DNA methylation patterns at imprinted loci in two classes of infertility. Fertility and Sterility, 94(5), 17281733. doi: 10.1016/j.fertnstert.2009.09.010 CrossRefGoogle ScholarPubMed
Holst, J. J. (2020). Incretin therapy for diabetes mellitus type 2. Current Opinion in Endocrinology, Diabetes, and Obesity, 27(1), 210. doi: 10.1097/MED.0000000000000516 CrossRefGoogle ScholarPubMed
Huypens, P., Sass, S., Wu, M., Dyckhoff, D., Tschöp, M., Theis, F., Marschall, S., Hrabě de Angelis, M. and Beckers, J. (2016). Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nature Genetics, 48(5), 497499. doi: 10.1038/ng.3527 CrossRefGoogle ScholarPubMed
Imani, M., Talebi, A. R., Fesahat, F., Rahiminia, T., Seifati, S. M. and Dehghanpour, F. (2021). Sperm parameters, DNA integrity, and protamine expression in patients with type II diabetes mellitus. Journal of Obstetrics and Gynaecology, 41(3), 439446. doi: 10.1080/01443615.2020.1744114 CrossRefGoogle ScholarPubMed
Kilarkaje, N., Al-Hussaini, H. and Al-Bader, M. M. (2014). Diabetes-induced DNA damage and apoptosis are associated with poly (ADP ribose) polymerase 1 inhibition in the rat testis. European Journal of Pharmacology, 737, 2940. doi: 10.1016/j.ejphar.2014.05.005 CrossRefGoogle ScholarPubMed
Kläver, R., Tüttelmann, F., Bleiziffer, A., Haaf, T., Kliesch, S. and Gromoll, J. (2013). DNA methylation in spermatozoa as a prospective marker in andrology. Andrology, 1(5), 731740. doi: 10.1111/j.2047-2927.2013.00118.x CrossRefGoogle ScholarPubMed
Kobayashi, H., Sato, A., Otsu, E., Hiura, H., Tomatsu, C., Utsunomiya, T., Sasaki, H., Yaegashi, N. and Arima, T. (2007). Aberrant DNA methylation of imprinted loci in sperm from oligospermic patients. Human Molecular Genetics, 16(21), 25422551. doi: 10.1093/hmg/ddm187 CrossRefGoogle ScholarPubMed
La Vignera, S., Condorelli, R., Vicari, E., D’Agata, R. and Calogero, A. E. (2012). Diabetes mellitus and sperm parameters. Journal of Andrology, 33(2), 145153. doi: 10.2164/jandrol.111.013193 CrossRefGoogle ScholarPubMed
Li, X. P., Hao, C. L., Wang, Q., Yi, X. M. and Jiang, Z. S. (2016). H19 gene methylation status is associated with male infertility. Experimental and Therapeutic Medicine, 12(1), 451456. doi: 10.3892/etm.2016.3314 CrossRefGoogle ScholarPubMed
Luján, S., Caroppo, E., Niederberger, C., Arce, J. C., Sadler-Riggleman, I., Beck, D., Nilsson, E. and Skinner, M. K. (2019). Sperm DNA methylation epimutation biomarkers for male infertility and FSH therapeutic responsiveness. Scientific Reports, 9(1), 16786. doi: 10.1038/s41598-019-52903-1 CrossRefGoogle ScholarPubMed
Marques, C. J., Costa, P., Vaz, B., Carvalho, F., Fernandes, S., Barros, A. and Sousa, M. (2008). Abnormal methylation of imprinted genes in human sperm is associated with oligozoospermia. Molecular Human Reproduction, 14(2), 6774. doi: 10.1093/molehr/gam093 CrossRefGoogle ScholarPubMed
Miller, D., Brinkworth, M. and Iles, D. (2010). Paternal DNA packaging in spermatozoa: More than the sum of its parts? DNA, histones, protamines and epigenetics. Reproduction, 139(2), 287301. doi: 10.1530/REP-09-0281 CrossRefGoogle Scholar
Mima, M., Greenwald, D. and Ohlander, S. (2018). Environmental toxins and male fertility. Current Urology Reports, 19(7), 50. doi: 10.1007/s11934-018-0804-1 CrossRefGoogle ScholarPubMed
Montjean, D., Ravel, C., Benkhalifa, M., Cohen-Bacrie, P., Berthaut, I., Bashamboo, A. and McElreavey, K. (2013). Methylation changes in mature sperm deoxyribonucleic acid from oligozoospermic men: Assessment of genetic variants and assisted reproductive technology outcome. Fertility and Sterility, 100(5), 12411247. e1242. doi: 10.1016/j.fertnstert.2013.06.047 CrossRefGoogle ScholarPubMed
Montjean, D., Zini, A., Ravel, C., Belloc, S., Dalleac, A., Copin, H., Boyer, P., McElreavey, K. and Benkhalifa, M. (2015). Sperm global DNA methylation level: Association with semen parameters and genome integrity. Andrology, 3(2), 235240. doi: 10.1111/andr.12001 CrossRefGoogle ScholarPubMed
Nasri, F., Gharesi-Fard, B., Namavar Jahromi, B., Farazi-Fard, M. A., Banaei, M., Davari, M., Ebrahimi, S. and Anvar, Z. (2017). Sperm DNA methylation of H19 imprinted gene and male infertility. Andrologia, 49(10), e12766. doi: 10.1111/and.12766 CrossRefGoogle ScholarPubMed
Poplinski, A., Tüttelmann, F., Kanber, D., Horsthemke, B. and Gromoll, J. (2010). Idiopathic male infertility is strongly associated with aberrant methylation of MEST and IGF2/H19 ICR1. International Journal of Andrology, 33(4), 642649. doi: 10.1111/j.1365-2605.2009.01000.x Google ScholarPubMed
Radford, E. J., Ito, M., Shi, H., Corish, J. A., Yamazawa, K., Isganaitis, E., Seisenberger, S., Hore, T. A., Reik, W., Erkek, S., Peters, A. H. F. M., Patti, M. E. and Ferguson-Smith, A. C. (2014). In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science, 345(6198), 1255903. doi: 10.1126/science.1255903 CrossRefGoogle ScholarPubMed
Rahat, B., Mahajan, A., Bagga, R., Hamid, A. and Kaur, J. (2017). Epigenetic modifications at DMRs of placental genes are subjected to variations in normal gestation, pathological conditions and folate supplementation. Scientific Reports, 7(1), 40774. doi: 10.1038/srep40774 CrossRefGoogle ScholarPubMed
Ribas-Maynou, J., García-Peiró, A., Fernández-Encinas, A., Abad, C., Amengual, M. J., Prada, E., Navarro, J. and Benet, J. (2013). Comprehensive analysis of sperm DNA fragmentation by five different assays: TUNEL assay, SCSA, SCD test and alkaline and neutral comet assay. Andrology, 1(5), 715722. doi: 10.1111/j.2047-2927.2013.00111.x CrossRefGoogle ScholarPubMed
Rodriguez-Martinez, H. (2007). Role of the oviduct in sperm capacitation. Theriogenology, 68 Suppl. 1, S138S146. doi: 10.1016/j.theriogenology.2007.03.018 CrossRefGoogle Scholar
Sakai, K., Ideta-Otsuka, M., Saito, H., Hiradate, Y., Hara, K., Igarashi, K. and Tanemura, K. (2018). Effects of doxorubicin on sperm DNA methylation in mouse models of testicular toxicity. Biochemical and Biophysical Research Communications, 498(3), 674679. doi: 10.1016/j.bbrc.2018.03.044 CrossRefGoogle ScholarPubMed
Santi, D., De Vincentis, S., Magnani, E. and Spaggiari, G. (2017). Impairment of sperm DNA methylation in male infertility: A meta-analytic study. Andrology, 5(4), 695703. doi: 10.1111/andr.12379 CrossRefGoogle ScholarPubMed
Satouh, Y. and Ikawa, M. (2018). New insights into the molecular events of mammalian fertilization. Trends in Biochemical Sciences, 43(10), 818828. doi: 10.1016/j.tibs.2018.08.006 CrossRefGoogle ScholarPubMed
Simas, J. N., Mendes, T. B., Fischer, L. W., Vendramini, V. and Miraglia, S. M. (2021). Resveratrol improves sperm DNA quality and reproductive capacity in type 1 diabetes. Andrology, 9(1), 384399. doi: 10.1111/andr.12891 CrossRefGoogle ScholarPubMed
Tunc, O. and Tremellen, K. (2009). Oxidative DNA damage impairs global sperm DNA methylation in infertile men. Journal of Assisted Reproduction and Genetics, 26(9–10), 537544. doi: 10.1007/s10815-009-9346-2 CrossRefGoogle ScholarPubMed
Valinluck, V., Tsai, H. H., Rogstad, D. K., Burdzy, A., Bird, A. and Sowers, L. C. (2004). Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Research, 32(14), 41004108. doi: 10.1093/nar/gkh739 CrossRefGoogle Scholar
Velker, B. A. M., Denomme, M. M., Krafty, R. T. and Mann, M. R. W. (2017). Maintenance of Mest imprinted methylation in blastocyst-stage mouse embryos is less stable than other imprinted loci following superovulation or embryo culture. Environmental Epigenetics, 3(3), dvx015. doi: 10.1093/eep/dvx015 CrossRefGoogle ScholarPubMed
Watkins, A. J., Dias, I., Tsuro, H., Allen, D., Emes, R. D., Moreton, J., Wilson, R., Ingram, R. J. M. and Sinclair, K. D. (2018). Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proceedings of the National Academy of Sciences, 115(40), 1006410069. doi: 10.1073/pnas.1806333115 CrossRefGoogle ScholarPubMed
Wei, Y., Yang, C. R., Wei, Y. P., Zhao, Z. A., Hou, Y., Schatten, H. and Sun, Q. Y. (2014). Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proceedings of the National Academy of Sciences of the United States of America, 111(5), 18731878. doi: 10.1073/pnas.1321195111 CrossRefGoogle ScholarPubMed
Wojdacz, T. K., Dobrovic, A. and Hansen, L. L. (2008). Methylation-sensitive high-resolution melting. Nature Protocols, 3(12), 19031908. doi: 10.1038/nprot.2008.191 CrossRefGoogle ScholarPubMed
Youngson, N. A., Lecomte, V., Maloney, C. A., Leung, P., Liu, J., Hesson, L. B., Luciani, F., Krause, L. and Morris, M. J. (2016). Obesity-induced sperm DNA methylation changes at satellite repeats are reprogrammed in rat offspring. Asian Journal of Andrology, 18(6), 930936. doi: 10.4103/1008-682X.163190 Google ScholarPubMed
Zhao, X., Chang, S., Liu, X., Wang, S., Zhang, Y., Lu, X., Zhang, T., Zhang, H. and Wang, L. (2020). Imprinting aberrations of SNRPN, ZAC1 and INPP5F genes involved in the pathogenesis of congenital heart disease with extracardiac malformations. Journal of Cellular and Molecular Medicine, 24(17), 98989907. doi: 10.1111/jcmm.15584 CrossRefGoogle ScholarPubMed