Changes in the Content of Small Non-Coding RNAs in Spermatozoa as a Possible Mechanism of Transgenerational Transmission of the Effects of Paternal Stress: Experimental Research

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

It has been proven that the stress of the father can affect the phenotype of offspring, causing somatic, behavioral, hormonal and molecular changes. One of the hypothetical mechanisms responsible for the transmission of paternal effects to offspring may be a change in the spectrum of regulatory non-coding RNAs in spermatozoa. In this paper, we investigated the effect of paternal stress in models of post-traumatic stress disorder (PTSD) and depression on the representation of small RNAs (micro- and piwiRNAs) in the sperm of stressed animals. Male Wistar rats were subjected to stress in two paradigms (“stress–restress” and “learned helplessness”), which leads to the development of PTSD-like and depressive-like states in model animals, respectively. 48 days after the restress, sperm preparations were received and RNA was isolated. The spectrum of small RNAs was studied by NGS sequencing. In males with a PTSD-like condition, a change in the expression of 27 piwi RNAs and 77 microRNAs was detected compared with the control group. Among the targets of these miRNAs, it is possible to identify genes whose products may be involved in such mechanisms of transmission of paternal effects to offspring as changes in DNA methylation, histone modifications and RNA interference (Dnmt3a, Setd5, Hdac1, Mllt10, Mtdh), as well as genes associated with the functioning of insulin-like growth factor 2, the expression of which as previously shown, it is altered in the central nervous system in the offspring of males with a PTSD-like condition (Igf2, Igf2bp2, Igf2r). No changes in the representation of small RNAs were registered in males with a simulated depression-like state. The results indicate a pronounced effect of paternal stress on the spectrum of short non-coding RNAs in sperm cells in rats, however, it depends on the nature of the stress effect.

About the authors

O. V. Malysheva

Pavlov Institute of Physiology, Russian Academy of Science; Ott Institute of Obstetrics, Gynecology, and Reproductology

Author for correspondence.
Email: omal99@mail.ru
Russia, 199034, St. Petersburg; Russia, 199034, St. Petersburg

S. G. Pivina

Pavlov Institute of Physiology, Russian Academy of Science

Email: omal99@mail.ru
Russia, 199034, St. Petersburg

E. N. Ponomareva

Ott Institute of Obstetrics, Gynecology, and Reproductology

Email: omal99@mail.ru
Russia, 199034, St. Petersburg

N. E. Ordyan

Pavlov Institute of Physiology, Russian Academy of Science

Email: omal99@mail.ru
Russia, 199034, St. Petersburg

References

  1. Ордян Н.Э., Малышева О.В., Холова Г.И., Акулова В.К., Пивина С.Г. 2021a. Зависимое от пола влияние стресса самцов крыс на память и экспрессию гена инсулиноподобного фактора роста 2 в мозге потомков. Журнал высшей нервной деятельности. Т. 71. № 3. С. 387. (Ordyan N.E., Malysheva O.V., Holova G.I., Akulova V.K., Pivina S.G. 2021. Sex-dependent influence of male rat stress on the memory and expression of the insulin-like growth factor 2 gene in the offspring brain. Zhurnal Vysshei Nervnoi Deyatelnosti imeni I. P. Pavlova. V. 71. № 3. P. 387.) https://doi.org/10.31857/S0044467721030060
  2. Ордян Н.Э., Малышева О.В., Акулова В.К., Холова Г.И., Пивина С.Г. 2021б. Нарушение когнитивных функций потомков самцов крыс, подвергнутых стрессированию в парадигмах “стресс−рестресс” или “выученная беспомощность”: роль инсулиноподобного фактора роста 2. Интегративная физиология. Т. 2. № 1. С.61. (Ordyan N.E., Malysheva O.V., Akulova V.K., Kholova G.I., Pivina S.G. 2021b. Cognitive impairment in the offspring of male rats exposed to stress in “stress – restress” or “learned helplessness” paradigms: The role of insulin-like growth factor 2. Integrative Physiology. V. 2. № 1. P. 61.) https://doi.org/10.33910/2687-1270-2021-2-1-61-70
  3. Пивина С.Г., Ракицкая В.В., Акулова В.К., Ордян Н.Э. 2015. Активность гипоталамо-гипофизарно-надпочечниковой системы пренатально стрессированных самцов крыс в экспериментальной модели посттравматического стрессового расстройства. Бюллетень экспер. биол. мед. Т. 160. № 11. С. 542. (Pivina S.G., Rakitskaya V.V., Akulova V.K., Ordyan N.E. 2016. Activity of the hypothalamic–pituitary–adrenal system in prenatally stressed male rats on the experimental model of post-traumatic stress disorder. Bull. Exper. Biol. Med. V. 160. P. 601.) https://doi.org/10.1007/s10517-016-3227-3
  4. Chen Q., Yan M., Cao Z., Li X., Zhang Y., Shi J., Feng G., Peng H., Zhang X., Zhang Y., Qian J., Duan E., Zhai Q., Zho Q. 2016. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science. V. 351. P. 397. https://doi.org/10.1126/science.aad7977
  5. Czech B., Munafó M., Ciabrelli F., Eastwood E.L., Fabry M.H., Kneuss E., Hannon G.J. 2018. piRNA-guided genome defense: from biogenesis to silencing. Annu. Rev. Genet. V. 52. P. 131. https://doi.org/10.1146/annurev-genet-120417-031441
  6. Czén B., Fuchs E., Wiborg O., Simon M. 2016. Animal models of major depression and their clinical implications. Progress Neuro-Psyhopharmacol. Biol. Psychiatry. V. 64. P. 293. https://doi.org/10.1016/j.pnpbp.2015.04.004
  7. Dietz D.M., LaPlant Q., Watts E.L., Hodes G.E., Russo S.J., Feng J., Oosting R.S., Vialou V., Nestler E.J. 2011. Paternal transmission of stress-induced pathologies. Biol. Psychiatry. V. 70. P. 408. https://doi.org/10.1016/j.biopsych.2011.05.005
  8. Dimofski P., Meyre D., Dreumont N., Leininger-Muller B. 2021. Consequences of paternal nutrition on offspring health and disease. Nutrients. V. 13. P. 2818. https://doi.org/10.3390/nu13082818
  9. Duffy K.A., Bale T.L., Epperson C.N. 2021. Germ cell drivers: transmission of preconception stress across generations. Front. Hum. Neurosci. V. 15. P. 642762. https://doi.org/10.3389/fnhum.2021.642762
  10. Franklin T.B., Russig H., Weiss I.C., Gräff J., Linder N., Michalon A., Vizi S., Mansuy I. 2010. Epigenetic transmission of the impact of early stress across generations. Biol. Psychiatry. V. 68. P. 408. https://doi.org/10.1016/j.biopsych.2010.05.036
  11. Frost R.J.A., Olson E.N. 2011. Control of glucose homeostasis and insulin sensitivity by the Let-7 family of microRNAs. Proc. Natl. Acad. Sci. USA. V. 108. P. 21075. https://doi.org/10.1073/pnas.1118922109
  12. Fullston T, Ohlsson Teague E.M., Palmer N.O., DeBlasio M.J., Mitchell M., Corbett M., Owens M. 2013. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. V. 27. P. 4226. https://doi.org/10.1096/fj.12-224048
  13. Gapp K., Jawaid A., Sarkies P., Bohacek J., Pelczar P., Prados J., Farinell L., Miska E., Mansuy I. 2014. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat. Neurosci. V. 17. P. 667. https://doi.org/10.1038/nn.3695
  14. Godia M., Swanson G., Krawetz S.A. 2018. A history of why fathers’ RNA matters. Biol. Reprod. V. 99. P. 147. https://doi.org/10.1093/biolre/ioy007
  15. Guo L., Chao S.-B., Xiao L., Wang Z.-B., Meng T.-G., Li Y.-Y., Han Z-M., Ouyang Y.-C., Hou Y, Sun Q.-Y., Ou X.-H. 2017. Sperm-carried RNAs play critical roles in mouse embryonic development. Oncotarget. V. 8. P. 67394. https://doi.org/10.18632/oncotarget.18672
  16. Harker A., Carroll C., Raza S., Kolb B., Gibb R. 2018. Preconception paternal stress in rats alters brain and behavior in offspring. Neurosci. V. 388. P. 474. https://doi.org/10.1016/j.neuroscience.2018.06.034
  17. Huang Y., Zhang J.L., Yu X.L., Xu T.S., Wang Z., Bin Z., Chao X. 2013. Molecular functions of small regulatory noncoding RNA. Biochemistry. V. 78. P. 221. https://doi.org/10.1134/S0006297913030024
  18. Jodar M., Selvaraju S., Sendler E., Diamond M.P., Krawetz S.A. 2013. The presence, role and clinical use of spermatozoal RNAs. Hum. Reprod. Update. V. 19. P. 604. https://doi.org/10.1093/humupd/dmt031
  19. Kamalidehghan B., Habibi M., Afjeh S.S., Shoai M., Alidoost S., Ghal R.A., Eshghifar N., Pouresmaeili F. 2020. The importance of small non-coding RNAs in human reproduction: a review article. Application Clinical Genetics. V. 13. P. 1. https://doi.org/10.2147/TACG.S207491
  20. Kiani J., Rassoulzadegan M. 2013. A load of small RNAs in the sperm – how many bits of hereditary information? Cell Res. V. 23. P. 18. https://doi.org/10.1038/cr.2012.181
  21. Love M.I., Huber W., Anders S. 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. V. 15. P. 550. https://doi.org/10.1186/s13059-014-0550-8
  22. Ly L., Chan D., Trasler J.M. 2015. Developmental windows of susceptibility for epigenetic inheritance through the male germline. Seminars Cell Devel. Biol. V. 43. P. 96. https://doi.org/10.1016/j.semcdb.2015.07.006
  23. Morgan C.P., Chan J.C., Bale T.L. 2019. Driving the next generation: paternal lifetime experiences transmitted via extracellular vesicles and their small RNA cargo. Biol. Psychiatry. V. 85. P. 164. https://doi.org/10.1016/j.biopsych.2018.09.007
  24. Morgan C.P., Shetty A.C., Chan J.C., Berger D.S., Ament S.A., Epperson C.N., Bale T.L. 2020. Repeated sampling facilitates within‑ and between‑subject modeling of the human sperm transcriptome to identify dynamic and stress‑responsive sncRNAs. Scientific Reports. V. 10. P. 17498. https://doi.org/10.1038/s41598-020-73867-7
  25. Ordyan N.E., Malysheva O.V., Akulova V.K., Pivina S.G., Kholova G.I. 2020. The capability to learn and expression of the insulin-like growth factor II gene in the brain of male rats whose fathers were subjected to stress factors in the “stress–restress” paradigm. Neurochem. J. V. 14. P. 191. https://doi.org/10.1134/S1819712420020075
  26. Ordyan N.E., Pivina S.G., Akulova V.K., Kholova G.I. 2021. Changes in the nature of behavior and the activity of the hypophyseal-adrenocortical system in the offspring of paternal rats subjected to stress in the stress–restress paradigm before mating. Neurosci. Behav. Physiol. V. 51. P. 528. https://doi.org/10.1007/s11055-021-01100-7
  27. Ozata D.M., Gainetdinov I., Zoch A., O’Caroll D., Zamore P.D. 2019. PIWI-interacting RNAs: small RNAs with big functions. Nat. Rev. Genet. V. 20. P. 89. https://doi.org/10.1038/s41576-018-0073-3
  28. Peng H., Shi J., Zhang Y., Zhang H., Liao S., Li W., Lei L., Han C., Ning L., Cao Y., Zhou Q., Chen Q., Duan E. 2012. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res. V. 22. P. 1609. https://doi.org/10.1038/cr.2012.141
  29. Rando O.J. 2012. Daddy issues: paternal effects on phenotype. Cell. V. 151. P. 702. https://doi.org/10.1016/j.cell.2012.10.020
  30. Rodgers A.B., Morgan C.P., Bronson S.L., Revello S., Bale T.L. 2013. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J. Neurosci. V. 33. P. 9003. https://doi.org/10.1523/JNEUROSCI.0914-13.2013
  31. Rodgers A.B., Bale T.L. 2015. Germ cell origins of posttraumatic stress disorder risk: the transgenerational impact of parental stress experience. Biol. Psychiatry. V. 78. P. 307. https://doi.org/10.1016/j.biopsych.2015.03.018
  32. Rodgers A.B., Morgan C.P., Leu N.A., Bale T.L. 2015. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc. Natl. Acad. Sci. USA. V. 112. P. 13699. https://doi.org/10.1073/pnas.1508347112
  33. Sharma A. 2013. Transgenerational epigenetic inheritance: Focus on soma to germline information transfer. Progress Biophysics Mol. Biology. V. 113. P. 439. https://doi.org/10.1016/j.pbiomolbio.2012.12.003
  34. Short A.K., Fennell K.A., Perreau V.M., Fox A., O’Bryan M.K., Kim J.H., Bredy T.W., Pang T.Y., Hannan A.J. 2016. Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring. Transl. Psychiatry. V. 6. P. e837. Ye
  35. Xavier M.J., Roman S.D., Aitken R.J., Nixon B. 2019. Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health. Hum. Reprod. Update. V. 25. P. 518. https://doi.org/10.1093/humupd/dmz017
  36. Yan W. 2014. Potential roles of noncoding RNAs in environmental epigenetic transgenerational inheritance. Mol. Cell. Endocrinol. V. 398. P. 24. https://doi.org/10.1016/j.mce.2014.09.008
  37. Yehuda R., Blair W., Labinsky E., Bierer L.M. 2007a. Effects of parental PTSD on the cortisol response to dexamethasone administration in their adult offspring. Am. J. Psychiatry. V. 164. P. 163. https://doi.org/10.1176/ajp.2007.164.1.163
  38. Yehuda R., Teicher M.H., Seckl J.R., Grossman R.A., Morris A., Bi-erer L.M. 2007b. Parental posttraumatic stress disorder as a vulnerability factor for low cortisol trait in offspring of Holocaust survivors. Archiv. Gen. Psychiatry. V. 64. P. 1040. https://doi.org/10.1001/archpsyc.64.9.1040
  39. Yeshurun S., Hannan A.J. 2019. Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders. Mol. Psychiatry. V. 24. P. 536. https://doi.org/10.1038/s41380-018-0039-z
  40. Yuan S., Schuster A., Tang C., Yu T., Ortogero N., Bao J., Zheng H., Yan W. 2016. Sperm-borne miRNAs and endo-siRNAs are important for fertilization and preimplantation embryonic development. Develop. V. 143. P. 635. https://doi.org/10.1242/dev.131755

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2.

Download (42KB)
Indexing metadata
3.

Download (585KB)
Indexing metadata

Copyright (c) 2023 О.В. Малышева, С.Г. Пивина, Е.Н. Пономарева, Н.Э. Ордян

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies