Tumor necrosis factor α knockout increases fertility of mice

Tumor necrosis factor alpha (TNF alpha) acts through two receptors, TNF alpha receptor vertical bar (TNFR vertical bar) and TNF alpha parallel to (TNFR parallel to). Tumor necrosis factor a receptor vertical bar knockout mice had early senescence and poor fertility, whereas TNFR parallel to knockout mice had reproductive performance not different from wild type (WT) mice. In the present study, TNF alpha knockout mice were used to study the roles of TNF alpha in female reproduction. The TNF alpha-/- 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 TNF alpha-/- 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, TNF alpha-/- mice had more estrous cycles than WT counterparts (6.0 +/- 0.25 vs 4.0 +/- 0.28, respectively, P < 0.05). Tumor necrosis factor a mutation also influenced ovarian follicular development; TNF alpha-/- 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 TNF alpha knockout affected growth of primordial follicles to the antral stage as well. Moreover, TNF alpha-/- 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 TNF alpha-/- mice was more than that in WT mice. These physiological differences in TNF alpha-/- mice were associated with increased proliferation of granulosa cells and decreased apoptosis of oocytes. This was apparently the first demonstration that in the TNF alpha-/- mouse model, multiple parameters of ovarian function were altered, and that lack of TNF alpha increased fertility in mice. (C) 2011 Elsevier Inc. All rights reserved.