Impact of telomere length and telomerase activity on the outcomes of assisted reproductive technology programs

Petrova O.V., Kirillova A.O., Nalobin D.S., Ushakova I.V., Abubakirov A.N.

1) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia; 2) M.V. Lomonosov Moscow State University, Moscow, Russia
This review describes the importance of telomeres and telomerase for human reproduction. It considers the impact of concomitant diseases on telomere length in females and males. It also describes telomerase activity and telomere length at different stages of ontogenesis: from spermatogenesis and oogenesis to subsequent embryonic development. There is information from various studies conducted within the framework of ART programs showing the relationship between telomere length, telomerase activity, and fertility. Many studies have shown that the length of telomeres in human germ cells has a positive effect on the formation and further development of embryos. The relationship between the length of telomere regions and fertility has also been demonstrated. For example, males with shorter telomeres have lower-quality embryos than those with longer sperm telomeres. Males with higher sperm DNA fragmentation are also observed to have a shorter telomere length. In women, the short telomere length is associated with different diseases. The presence of elongated telomeres in the oocytes has shown that the probability of forming good-quality embryos increases.
Conclusion. The role of telomere length and telomerase activity in the germ cells can make it possible to predict the effectiveness of ART programs and to introduce new analyses aimed at finding the causes of male and female infertility in future.

Keywords

telomeres
telomerase
sperm telomere length
oocyte telomere length
ART
IVF

References

  1. Егоров Е.Е. Теломеры, теломераза, канцерогенез и мера здоровья. Клиническая онкогематология. Фундаментальные исследования и клиническая практика. 2010; 3(2): 184-97. [Egorov E.E. Telomeres, telomerase, carcinogenesis and health measure. Clinical hematology oncology. 2010; 3 (2): 184-97. (in Russian)].
  2. Hayflick L., Moorhead P.S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 1961; 25: 585-621. https://dx.doi.org/10.1016/0014-4827(61)90192-6.
  3. Оловников А.М. Принцип маргинотомии в матричном синтезе полинуклеотидов. Доклады Академии наук СССР. 1971; 201(6): 1496-9. [Olovnikov A.M. The principle of marginotomy in the matrix synthesis of polynucleotides. Doс. Acad. 1971; 201: 1496-9. (in Russian)].
  4. Оловников А.М. Иммунный ответ и процесс маргинотомии в лимфоидных клетках. Вестник АМН СССР. 1972; 12: 85-7. [Olovnikov A.M. Immune response and marginotomy process in lymphoid cells. Bulletin of the USSR Academy of Medical Sciences. 1972; 12: 85-7. (in Russian)].
  5. Oeseburg H., de Boer R.A., van Gilst W.H., van der Harst P. Telomere biology in healthy aging and disease. Pflugers Arch. 2010; 459(2): 259-68. https://dx.doi.org/10.1007/s00424-009-0728-1.
  6. Rocca M.S., Foresta C., Ferlin A. Telomere length: lights and shadows on their role in human reproduction. Biol. Reprod. 2019; 100(2): 305-17. https://dx.doi.org/10.1093/biolre/ioy208.
  7. Parks C.G., DeRoo L.A., Miller D.B., McCanlies E.C., Cawthon R.M., Sandler D.P. Employment and work schedule are related to telomere length in women. Occup. Environ. Med. 2011; 68(8): 582-9. https://dx.doi.org/10.1136/oem.2010.063214.
  8. Kim N.W., Piatyszek M.A., Prowse K.R., Harley C.B., West M.D., Ho P.L. et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266(5193): 2011-5. https://dx.doi.org/10.1136/oem.2010.06321410.1126/science.7605428.
  9. Riethman H. Human telomere structure and biology. Annu. Rev. Genomics Hum. Genet. 2008; 9: 1-19. https://dx.doi.org/10.1146/annurev.genom.8.021506.172017.
  10. Keefe D.L., Liu L. Telomeres and reproductive aging. Reprod. Fertil. Dev. 2009; 21(1): 10-4. https://dx.doi.org/10.1071/RD08229.
  11. Reig-Viader R., Brieno-Enrıquez M.A., Khoriauli L., Toran N., Cabero L., Giulotto E. et al. Telomeric repeat-containing RNA and telomerase in human fetal oocytes. Hum. Reprod. 2013; 28(2): 414-22. https://dx.doi.org/10.1093/humrep/des363.
  12. Reig-Viader R., Vila-Cejudo M., Vitelli V., Busca R., Sabate M., Giulotto E. et al. Telomeric repeat-containing RNA (TERRA) and telomerase are components of telomeres during mammalian gametogenesis. Biol. Reprod. 2014; 90(5): 103. https://dx.doi.org/10.1095/biolreprod.113.116954.
  13. Achi M.V., Ravindranath N., Dym M. Telomere length in male germ cells is inversely correlated with telomerase activity. Biol. Reprod. 2000; 63(2): 591-8. https://dx.doi.org/10.1095/biolreprod63.2.591.
  14. Turner S., Hartshorne G.M. Telomere lengths in human pronuclei, oocytes and spermatozoa. Mol. Hum. Reprod. 2013; 19(8): 510-8. https://doi.org/10.1093/molehr/gat021.
  15. Bryan T.M., Englezou A., Gupta J., Bacchetti S., Reddel R.R. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 1995; 14(17): 4240-8.
  16. Reddel R.R., Bryan T.M., Colgin L.M., Perrem K.T., Yeager T.R. Alternative lengthening of telomeres in human cells. Radiat. Res. 2001; 155(1): 194-200. https://dx.doi.org/10.1667/0033-7587(2001)155[0194:ALOTIH]2.0.CO;2.
  17. Henson J.D., Neumann A.A., Yeager T.R., Reddel R.R. Alternative lengthening of telomeres in mammalian cells. Oncogene. 2002; 21(4): 598-610. https://dx.doi.org/10.1038/sj.onc.1205058.
  18. Lafuente R., Bosch-Rue E., Ribas-Maynou J., Alvarez J., Brassesco C., Amengual M.J. et al. Sperm telomere length in motile sperm selection techniques: a qFISH approach. Andrologia. 2018; 50(2): e12840. https://dx.doi.org/10.1111/and.12840.
  19. Martens U.M., Chavez E.A., Poon S.S., Schmoor C., Lansdorp P.M. Accumulation or short telomeres in human fibroblasts prior to replicative senescence. Exp. Cell Res. 2000; 256(1): 291-9. https://dx.doi.org/10.1006/excr.2000.4823.
  20. de Frutos C., Lopez-Cardona A.P., Fonseca Balvıs N., Laguna-Barraza R., Rizos D., Gutierrez-Adan A. et al. Spermatozoa telomeres determine telomere length in early embryos and offspring. Reproduction. 2016; 151(1): 1-7. https://dx.doi.org/10.1530/REP-15-0375.
  21. Prescott J., Du M., Wong J.Y.Y., Han J., De Vivo I. Paternal age at birth is associated with offspring leukocyte telomere length in the nurses’ health study. Hum. Reprod. 2012; 27(12): 3622-31. https://dx.doi.org/10.1093/humrep/des314.
  22. Aviv A., Susser E. Leukocyte telomere length and the Father’s age enigma: implications for population health and for life course. Int. J. Epidemiol. 2013; 42(2): 457-62. https://dx.doi.org/10.1093/ije/dys236.
  23. Eisenberg D.T., Hayes M.G., Kuzawa C.W. Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants. Proc. Natl. Acad. Sci. USA. 2012; 109(26): 10251-6. https://dx.doi.org/10.1073/pnas.1202092109.
  24. Ferlin A., Rampazzo E., Rocca M.S., Keppel S., Frigo A.C., De Rossi A. et al. In young men sperm telomere length is related to sperm number and parental age. Hum. Reprod. 2013; 28(12): 3370-6. https://dx.doi.org/10.1093/humrep/det392.
  25. Yang Q., Zhao F., Dai S., Zhang N., Zhao W., Bai R. et al. Sperm telomere length is positively associated with the quality of early embryonic development. Hum. Reprod. 2015; 30(8): 1876-81. https://dx.doi.org/10.1093/humrep/dev144.
  26. Yang Q., Zhang N., Zhao F., Zhao W., Dai S., Liu J. et al. Processing of semen by density gradient centrifugation selects spermatozoa with longer telomeres for assisted reproduction techniques. Reprod. Biomed. Online. 2015; 31(1): 44-50. https://dx.doi.org/10.1016/j.rbmo.2015.02.016.
  27. Santiso R., Tamayo M., Gosalvez J., Meseguer M., Garrido N., Fernandez J.L.Swim-up procedure selects spermatozoa with longer telomere length. Mutat. Res. 2010; 688(1-2): 88-90. https://dx.doi.org/10.1016/j.mrfmmm.2010.03.003.
  28. Rocca M.S., Speltra E., Menegazzo M., Garolla A., Foresta C., Ferlin A. Sperm telomere length as a parameter of sperm quality in normozoospermic men. Hum. Reprod. 2016; 31(6): 1158-63. https://dx.doi.org/10.1093/humrep/dew061.
  29. Berneau S.C., Shackleton J., Nevin C., Altakroni B., Papadopoulos G., Horne G. et al. Associations of sperm telomere length with semen parameters, clinical outcomes and lifestyle factors in human normozoospermic samples. Andrology. 2020; 8(3): 583-93. https://dx.doi.org/10.1111/andr.12734.
  30. Ma H., Zhou Z., Wei S., Liu Z., Pooley K.A., Dunning A.M. et al. Shortened telomere length is associated with increased risk of cancer: a meta-analysis. PLoS One. 2011; 6(6): e20466. https://dx.doi.org/10.1371/journal.pone.0020466.
  31. Haycock P.C., Heydon E.E., Kaptoge S., Butterworth A.S., Thompson A., Willeit P. Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2014; 349: g4227. https://dx.doi.org/10.1136/bmj.g4227.
  32. Willeit P., Raschenberger J., Heydon E.E., Tsimikas S., Haun M., Mayr A. et al. Leucocyte telomere length and risk of type 2 diabetes mellitus: New prospective cohort study and literature‑based meta-analysis. PLoS One. 2014; 9(11): e112483. https://dx.doi.org/10.1371/journal.pone.0112483.
  33. Aviv A., Kark J.D., Susser E. Telomeres, atherosclerosis, and human longevity: a causal hypothesis. Epidemiology. 2015; 26(3): 295-9. https://dx.doi.org/10.1097/EDE.0000000000000280.
  34. Zhang J., Rane G., Dai X., Shanmugam M.K., Arfuso F., Samy R.P. et al. Ageing and the telomere connection: an intimate relationship with inflammation. Ageing Res. Rev. 2016; 25: 55-69. https://dx.doi.org/10.1016/j.arr.2015.11.006.
  35. Ghosh S., Feingold E., Chakraborty S., Dey S.K. Telomere length is associated with types of chromosome 21 nondisjunction: a new insight into the maternal age effect on Down syndrome birth. Hum. Genet. 2010; 127(4): 403-9. https://dx.doi.org/10.1007/s00439-009-0785-8.
  36. Dorland M., van Montfrans J.M., van Kooij R.J., Lambalk C.B., te Velde E.R. Normal telomere lengths in young mothers of children with Down’s syndrome. Lancet. 1998; 352(9132): 961-2. https://dx.doi.org/10.1016/S0140-6736(05)61516-4.
  37. Hanna C.W., Bretherick K.L., Gair J.L., Fluker M.R., Stephenson M.D., Robinson W.P. Telomere length and reproductive aging. Hum. Reprod. 2009; 24(5): 1206-11. https://dx.doi.org/10.1093/humrep/dep007.
  38. Butts S., Riethman H., Ratcliffe S., Shaunik A., Coutifaris C., Barnhart K. Correlation of telomere length and telomerase activity with occult ovarian insufficiency. J. Clin. Endocrinol. Metab. 2009; 94(12): 4835-43. https://dx.doi.org/10.1210/jc.2008-2269.
  39. Xu X., Chen X., Zhang X., Liu Y., Wang Z., Wang P. et al. Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency. Hum. Reprod. 2017; 32(1): 201-7. https://dx.doi.org/10.1093/humrep/dew283.
  40. Hapangama D.K., Turner M.A., Drury J., Heathcote L., Afshar Y., Mavrogianis P.A. et al. Aberrant expression of regulators of cell-fate found in eutopic endometrium is found in matched ectopic endometrium among women and in a baboon model of endometriosis. Hum. Reprod. 2010; 25(11): 2840-50. https://dx.doi.org/10.1093/humrep/deq248.
  41. Kalyan S., Patel M.S., Kingwell E., Côté H.C.F., Liu D., Prior J.C. Competing factors link to bone health in polycystic ovary syndrome: chronic low-grade inflammation takes a toll. Sci. Rep. 2017; 7(1): 3432. https://dx.doi.org/10.1038/s41598-017-03685-x.
  42. Miranda-Furtado C.L., Ramos F.K., Kogure G.S., Santana-Lemos B.A., Ferriani R.A., Calado R.T. et al. A nonrandomized trial of progressive resistance training intervention in women with polycystic ovary syndrome and its implications in telomere content. Reprod. Sci. 2016; 23(5): 644-54. https://dx.doi.org/10.1177/1933719115611753.
  43. Wei D., Xie J., Yin B., Hao H., Song X., Liu Q. et al. Significantly lengthened telomere in granulosa cells from women with polycystic ovarian syndrome (PCOS). J. Assist. Reprod. Genet. 2017; 34(7): 861-6. https://dx.doi.org/10.1007/s10815-017-0945-z.
  44. Wang C., Shen F., Zhu Y., Fang Y., Lu S. Telomeric repeat-containing RNA (TERRA) related to polycystic ovary syndrome (PCOS). Clin. Endocrinol. (Oxf). 2017; 86(4): 552-9. https://dx.doi.org/10.1111/cen.13283.
  45. Li Q., Du J., Feng R., Xu Y., Wang H., Sang Q. et al. A possible new mechanism in the pathophysiology of polycystic ovary syndrome (PCOS): the discovery that leukocyte telomere length is strongly associated with PCOS. J. Clin. Endocrinol. Metab. 2014; 99(2): E234-40. https://dx.doi.org/10.1210/jc.2013-3685.
  46. Li Y., Deng B., Ouyang N., Yuan P., Zheng L., Wang W. Telomere length is short in PCOS and oral contraceptive does not affect the telomerase activity in granulosa cells of patients with PCOS. J. Assist. Reprod. Genet. 2017; 34(7): 849-59. https://dx.doi.org/10.1007/s10815-017-0929-z.
  47. Sofiyeva N., Ekizoglu S., Gezer A., Yilmaz H., Kolomuc Gayretli T., Buyru N. et al. Does telomerase activity have an effect on infertility in patients with endometriosis? Eur. J. Obstet. Gynecol. Reprod. Biol. 2017; 213: 116-22. https://dx.doi.org/10.1016/j.ejogrb.2017.04.027.
  48. Valentijn A.J., Saretzki G., Tempest N., Critchley H.O., Hapangama D.K. Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis. Hum. Reprod. 2015; 30(12): 2816-28. https://dx.doi.org/10.1093/humrep/dev267.
  49. Williams C.D., Boggess J.F., LaMarque L.R., Meyer W.R., Murray M.J.,Fritz M.A. et al. A prospective, randomized study of endometrial telomerase during the menstrual cycle. J. Clin. Endocrinol. Metab. 2001; 86(8): 3912-7. https://dx.doi.org/10.1210/jcem.86.8.7729.
  50. Kalmbach K.H., Antunes D.M., Kohlrausch F., Keefe D.L. Telomeres and female reproductive aging. Semin. Reprod. Med. 2015; 33(6): 389-95. https://dx.doi.org/10.1055/s-0035-1567823.
  51. Keefe D.L., Liu L., Marquard K. Telomeres and aging-related meiotic dysfunction in women. Cell. Mol. Life Sci. 2007; 64(2): 139-43. https://dx.doi.org/10.1007/s00018-006-6466-z.
  52. Keefe D.L., Franco S., Liu L., Trimarchi J., Cao B., Weitzen S. et al. Telomere length predicts embryo fragmentation after in vitro fertilization in women – toward a telomere theory of reproductive aging in women. Am. J. Obstet. Gynecol. 2005; 192(4): 1256-61; discussion 1260-1. https://dx.doi.org/10.1016/j.ajog.2005.01.036.
  53. Treff N.R., Su J., Taylor D., Scott R.T. Jr. Telomere DNA deficiency is associated with development of human embryonic aneuploidy. PLoS Genet. 2011; 7(6): e1002161. https://dx.doi.org/10.1371/journal.pgen.1002161.
  54. Wright W.E., Piatyszek M.A., Rainey W.E., Byrd W., Shay J.W. Telomerase activity in human germ line and embryonic tissues and cells. Dev. Genet. 1996; 18(2): 173-9. https://dx.doi.org/10.1002/(SICI)1520-6408(1996)18:2<173::AID-DVG10>3.0.CO;2-3.
  55. Liu L., Bailey S.M., Okuka M., Munoz P., Li C., Zhou L. et al. Telomere lengthening early in development. Nat. Cell Biol. 2007; 9(12): 1436-41. https://dx.doi.org/10.1038/ncb1664.
  56. Iqbal K., Kues W.A., Baulain U., Garrels W., Herrmann D., Niemann H. Species-specific telomere length differences between blastocyst cell compartments and ectopic telomere extension in early bovine embryos by human telomerase reverse transcriptase. Biol. Reprod. 2011; 84(4): 723-33. https://dx.doi.org/10.1095/biolreprod.110.087205.
  57. Schaetzlein S., Lucas-Hahn A., Lemme E., Kues W.A., Dorsch M., Manns M.P. et al. Telomere length is reset during early mammalian embryogenesis. Proc. Natl. Acad. Sci. USA. 2004; 101(21): 8034-8. https://dx.doi.org/10.1073/pnas.0402400101.

Received 24.08.2020

Accepted 29.10.2020

About the Authors

Olga V. Petrova, junior researcher of 1st gynecology department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of Russian Federation. Тel.: +7(917)533-32-08. Е-mail: olga.zaharkina.90@mail.ru. 117997, Russia, Mosсow, Ac. Oparina str., 4.
Anastasia O. Kirillova, PhD, senior researcher of 1st gynecology department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of Russian Federation. , Е-mail: stasia.kozyreva@gmail.com. 117997, Russia, Mosсow, Ac. Oparina str., 4.
Denis S. Nalobin, PhD, senior researcher of Laboratory of Prototyping and Testing of Biological Developments, Faculty of Biology; Associate Professor, Faculty of Biotechnology, M.V. Lomonosov Moscow State University. Tel: +7(495)939-33-35. E-mail: denis.nalobin@gmail.com. 119991, Russia, Mosсow, Leninskije gory, 1.
Irina V. Ushakova, PhD, embryologist of 1-st gynecology department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of Russian Federation. Тel.: +7(495)438-26-22. Е-mail: irisun77@mail.ru. 117997, Russia, Mosсow, Ac. Oparina str., 4.
Aidar N. Abubakirov, PhD, Head of 1st gynecology department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of Russian Federation. Тel.: +7(495)438-26-22. Е-mail: nondoc555@yahoo.com. 117997, Russia, Mosсow, Ac. Oparina str., 4.

For citation: Petrova O.V., Kirillova A.O., Nalobin D.S., Ushakova I.V., Abubakirov A.N. Impact of telomere length and telomerase activity on the outcomes of assisted reproductive technology programs.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2020; 11: 49-54 (in Russian).
https://dx.doi.org/10.18565/aig.2020.11.49-54

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