Reproductive effects of the tumor necrosis factor (TNF) deficiency in mice. S. O. Maslennikova, G. V. Kontsevaya, M. A. Zolotykh, M. V. Anisimova, N. A. Feofanova, M. P. Moshkin, S. A. Nedospasov, L. A. Gerlinskaya


TNF is a multifunctional cytokine that, at physiological concentrations, maintains the balance between apoptosis and survival of male germ cells and, at higher concentrations, has adverse effects on various stages of the reproductive process. Although ant-cytokine therapies have been used in millions of patients, the consequences of cytokine deficiency for reproductive functions are poorly understood and need attention. In this work, we have studied behavioral interactions between males and females, spermatogenesis, male fertility, and embryonic developmental characteristics of the progeny in TNFα knockout mice (TNF-/-). We have demonstrated that TNF is involved in the regulation of sexual behavior, spermatogenesis, pre- and postimplantation development. Complete TNF deficiency led to decreased reproductive efficiency: a lower number of viable embryos were observed in TNF-/- mice than in wild-type mice. The decrease in fertility was caused by preimplantation embryo loss in TNF-/- mice. Preimplantation loss in females might be caused by asospermia in TNF-/- males. Additionally, the sensitivity of reproductive functions to female stimuli was different between TNF-/- mice and wild-type mice, while interactions with females increased the concentrations of sper­matozoids in both TNF-/- and wild-type mice. Still higher levels were observed in knockout animals, which led to increase in the number of immature spermatozoids in epididymides.

About The Authors:

S. O. Maslennikova. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

G. V. Kontsevaya. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

M. A. Zolotykh. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

M. V. Anisimova. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

N. A. Feofanova. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

M. P. Moshkin. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk

S. A. Nedospasov. Engelhardt Institute of Molecular Biology Russian Academy of Sciences; Lomonosov Moscow State University, Russian Federation, Moscow

L. A. Gerlinskaya. Institute of Cytology and Genetics SB RAS, Russian Federation, Novosibirsk


1. Agarwal A., Sharma R.K., Nelson D.R. New semen quality scores developed by principal component analysis of semen characteristics. J. Androl. 2003;24(3):343-352.

2. Astrakhantseva I.V., Efimov G.A., Drutskaya M.S., Kruglov A.A., Nedospasov S.A. Modern anti-cytokine therapy of autoimmune diseases. Biokhimiya — Biochemistry. 2014;12:1605-1616.

3. Bulletti C., Flamigni C., Giacomucci E. Reproductive failure due to spontaneous abortion and recurrent miscarriage. Hum. Reprod. Update. 1996;2(2):P.118-136.

4. Drutskaya M.S., Efimov G.A., Zvartsev R.V., Chashchina A.A., Chudakov D.M., Tillib, S.V., Kruglov A.A., Nedospasov S.A.. Experimental models of arthritis in which pathogenesis is dependent on TNF expression. Biokhimiya — Biochemistry. 2014;12:1648-1656.

5. Grivennikov S.I., Tumanov A.V., Liepinsh D.J., Kruglov A.A., Marakusha B.I., Shakhov A.N., Murakami T., Druts­kaya L.N., Förster I., Clausen B.E., Tessarollo L., Ryffel B., Kuprash D.V., Nedospasov S.A. Distinct and nonredundant Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity. 2005;22(1):93-104.

6. Holdcraft R.W., Braun R.E. Hormonal regulation of spermatogenesis. Intern. J. Androl. 2004;27:335-342.

7. McLachlan R.I., Wreford N.G., Meachem S.J., De Kretser D.M., Robertson D.M. Effects of testosterone on spermatogenic cell popu Effects of testosterone on spermatogenic cell populations in the adult rat. Biol. Reprod. 1994;51(5):945-955.

8. Moshkin M.P., Gerlinskaya L.A., Evsikov V.I. The role of the immune system in behavioural strategies of reproduction. J. Reprod. Dev. 2000;46:341-365.

9. Pentikäinen V., Erkkilä K., Suomalainen L., Otala M., Pentikäinen M.O., Parvinen M., Dunkel L. TNF alpha down-regulates the Fasligand and inhibits germ cell apoptosis in the human testis J. Clin. Endocrinol. Metab. 2001;86(9):4480-4488

10. Perdichizzi A., Nicoletti F., La Vignera S., Barone N., D’Agata R., Vicari E., Calogero A. Effects of tumour necrosis factor-α on human sperm motility and apoptosis. J. Clin. Immunol. 2007;27:341-365.

11. Pérez C.V., Theas M.S., Jacobo P.V., Jarazo-Dietrich S., Guazzone V.A., Lustig L. Dual role of immune cells in the testis. Spermatogenesis. 2013;3(1):e23870. DOI: 10.4161

12. Perry G., Cash A.D., Smith M.A. Alzheimer disease and oxidative stress. J. Biomed. Biotechnol. 2002;2(3):120-123.

13. Prather A.A., Rabinovitz M., Pollock B.G., Lotrich F.E. Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain Behav. Immun. 2009;23(8):1109-1116. DOI:10.1016/j.bbi.2009

14. Raison C.L., Rye D.B., Woolwine B.J., Vogt G.J., Bautista B.M., Spivey J.R., Miller A.H. Chronic interferon-alpha administration disrupts sleep continuity and depth in patients with hepatitis C: association with fatigue, motor slowing, and increased evening cortisol. Biol. Psychiatry. 2010;15(10):942-949. DOI:10.1016/j.biopsych.2010

15. Ramón M., Soler A.J., Ortiz J.A., García-Alvarez O., Maroto-Morales A., Roldan E.R.S., Garde J.J. Sperm population structure and male fertility. Biol. Reprod. 2013;7(89):110.

16. Riccioli A., Starace D., D’Alessio A., Starace G., Padula F., De Cesaris P., Filippini A., Ziparo E. TNF-alpha and IFN-gamma regulate expression and function of the Fas system in the seminiferous epithelium. J. Immunol. 2000;15(165):743-749.

17. Suh J.H., Gong E.Y., Hong C.Y., Park E., Ahn R.S., Park K.S., Lee K. Reduced testicular steroidogenesis in tumor necrosis factor-alpha knockout mice. J. Steroid Biochem. Mol. Biol. 2008;112(1/3): 117-121.

18. Sultan B., May L.A., Lane A. P. The role of TNF-α in inflammatory olfactory loss. Laryngoscope. 2011;121(11):2481-2486.

19. Suominen J.S., Wang Y., Kaipia A., Toppari J. Tumor necrosis factoralpha (TNF-alpha) promotes cell survival during spermatogenesis, and this effect can be blocked by infliximab, a TNF-alpha antagonist. Eur. J. Endocrinol. 2004;151(5):629-640.

20. Theas M.S., Rival C., Jarazo-Dietrich S., Jacobo P., Guazzone V.A., Lustig L. Tumour necrosis factor-a released by testicular macrophages induces apoptosis of germ cells in autoimmune orchitis. Hum. Reprod. 2008;23(8):1865-1872.

21. Volkova O.V., Eletskii Yu.K. Osnovy gistologii s gistologicheskoy tekh­nikoy [Basics of histology and histological methods]. Moscow, Meditsina, 2008. 304 p.

22. Wosnitzer M., Goldstein M., Hardy M.P. Review of Azoospermia. Review of Azoospermia.

23. Spermatogenesis. 2014;31(4):e28218.

24. Wride M.A., Sanders E.J. Potential roles for tumour necrosis factor alpha during embryonic development. Anat. Embryol. (Berl). 1995;191(1):1-10.

25. Zalcman S.S., Siegel A. The neurobiology of aggression and rage: role of cytokines. Brain Behav. Immun. 2006;20(6):507-514.

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