Tumor necrosis factor α knockout increases fertility of mice

• Published in: Theriogenology Vol. 75; no. 5; pp. 867 - 876
• Main Authors: Cui, Lan-lan, Yang, Guiwen, Pan, Jie, Zhang, Cong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2011; [Oxford]: Butterworth-Heinemann; [New York]: Elsevier Science
• Subjects: analysis; anatomy & histology; animal models; Animals; apoptosis; Breeding; Caspase 3; Caspase 3 - analysis; chemistry; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 4 - analysis; deficiency; drug effects; Estrous Cycle; Estrous Cycle - physiology; Female; Fertility; Fertility - physiology; follicular development; Gonadotropins; Gonadotropins - pharmacology; Granulosa cell; granulosa cells; Growth factor; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mutation; necrosis; Oocyte; oocytes; Ovarian Follicle; Ovarian Follicle - physiology; Ovary; Ovary - anatomy & histology; Ovary - chemistry; Ovulation; Ovulation - drug effects; parturition; pharmacology; physiology; pups; receptors; Reproduction; Reproduction - physiology; reproductive performance; Sexual Maturation; Sexual Maturation - physiology; TNFα; Tumor Necrosis Factor-alpha; Tumor Necrosis Factor-alpha - deficiency; Tumor Necrosis Factor-alpha - physiology; Granulosa cell; TNFα; Ovarian follicle; Oocyte; Growth factor
• ISSN: 0093-691X; 1879-3231; 1879-3231
• DOI: 10.1016/j.theriogenology.2010.10.029

Tumor necrosis factor α (TNFα) acts through two receptors, TNFα receptor| (TNFR|) and TNFα‖ (TNFR‖). Tumor necrosis factor α receptor| knockout mice had early senescence and poor fertility, whereas TNFR‖ knockout mice had reproductive performance not different from wild type (WT) mice. In the present study, TNFα knockout mice were used to study the roles of TNFα in female reproduction. The TNFα−/− mice had similar vaginal opening time (PD 27.6 ± 1.8 vs PD 27.7 ± 1.9, respectively, P > 0.05) and exogenous gonadotropin primed TNFα−/− mice shed more ova (28.9 ± 3.75 vs 9.8 ± 0.51, respectively, P = 0.001) compared with WT controls. At 2 mo of age, in 21 d, TNFα−/− mice had more estrous cycles than WT counterparts (6.0 ± 0.25 vs 4.0 ± 0.28, respectively, P < 0.05). Tumor necrosis factor α mutation also influenced ovarian follicular development; TNFα−/− mice had approximately a two-fold larger follicle pool in the early neonatal period (6087 ± 508.15 vs 3440 ± 261.91, respectively, P = 0.004), whereas TNFα knockout affected growth of primordial follicles to the antral stage as well. Moreover, TNFα−/− mice gave birth to 21% more pups than control mice during a 12 mo breeding period (37.38 ± 3.69 vs 22.38 ± 3.53, respectively, P = 0.03). At 1 y of age, the follicular reserve in TNFα−/− mice was more than that in WT mice. These physiological differences in TNFα−/− mice were associated with increased proliferation of granulosa cells and decreased apoptosis of oocytes. This was apparently the first demonstration that in the TNFα−/− mouse model, multiple parameters of ovarian function were altered, and that lack of TNFα increased fertility in mice.