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Alterations of events related to ovarian function in tumor necrosis factor receptor type I knockout mice
K F Roby1, D S Son, P F Terranova
1Departments of Anatomy and Cell Biology, Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, 66160, USA.
Abstract:
C57BL6 mice with targeted disruption of tumor necrosis factor (TNF) type 1 receptor (TNFRI) exhibited early vaginal opening when compared with wild-type mice (Day 24 +/- 0.6, n = 10, vs. 28 +/- 0.2, n = 11, P < 0.001). Equine CG- and hCG-treated TNFRI null mice ovulated more ova than did controls at two distinct times during the prepubertal period (Day 21: 13.4 +/- 1.7 vs. 7.3 +/- 1.4, P < 0.05; Day 25: 20.7 +/- 2.7 vs. 13.0 +/- 1.3, P < 0.05). Enhanced responsiveness to gonadotropins was not observed in adult mice. At 6 mo of age only 40% of TNFRI null mice exhibited estrous cycles. Those TNFRI null mice with estrous cycles spent significantly more time in diestrus and less time in estrus than controls. TNFRI null mice delivered significantly fewer litters (P < 0.001) than did C57BL6 and TNFRII null mice (TNFRI null 2.59 +/- 0.39; C57BL6 4.91 +/- 0.57; TNFRII null 5.40 +/- 0.60 litters/mo/10 pairs over a 12-mo period). Ovarian dispersates prepared on Day 25 of age from control and TNFRI knockout mice were cultured with and without 10 ng TNF/ml. TNF inhibited LH-stimulated progesterone and estradiol secretion by control dispersates but had no effect on cAMP. In contrast, TNF did not affect LH-stimulated accumulation of progesterone, estradiol, or cAMP by ovarian dispersates from TNFRI knockout mice. The results indicate that lack of TNFRI enhances ovarian responsiveness to gonadotropins during the prepubertal period and may be related to early vaginal opening. The lack of TNFRI is associated with early senescence and poor fertility. These studies demonstrate that the mechanism of TNF-mediated inhibition of steroidogenesis is most likely via TNFRI.
Insights
Mice lacking the tumor necrosis factor type 1 receptor (TNFRI) showed early puberty and enhanced ovarian response to hormones. However, these mice experienced premature aging and reduced fertility, indicating TNFRI
Area of Science:
- Reproductive Endocrinology
- Immunology
- Molecular Biology
Background:
- Tumor necrosis factor (TNF) is a cytokine involved in immune responses and inflammation.
- The role of TNF and its receptors in reproductive processes is not fully understood.
- Tumor necrosis factor type 1 receptor (TNFRI) mediates the effects of TNF.
Purpose of the Study:
- To investigate the role of TNFRI in female reproductive development and function.
- To determine the impact of TNFRI deficiency on puberty, ovulation, estrous cycles, and fertility.
- To elucidate the mechanism of TNF-induced inhibition of steroidogenesis.
Main Methods:
- Comparison of C57BL6 mice with targeted disruption of TNFRI (TNFRI null) versus wild-type mice.
- Assessment of vaginal opening, ovulation rates after gonadotropin treatment, estrous cyclicity, and litter size.
- In vitro culture of ovarian dispersates to assess the effect of TNF on LH-stimulated steroidogenesis and cAMP production.
Main Results:
- TNFRI null mice exhibited significantly earlier vaginal opening compared to wild-type controls.
- Prepubertal TNFRI null mice showed enhanced ovulation in response to equine CG and hCG.
- Adult TNFRI null mice displayed disrupted estrous cycles, reduced fertility, and signs of early senescence.
- TNFRI deficiency abolished the inhibitory effect of TNF on LH-stimulated progesterone and estradiol secretion in vitro.
Conclusions:
- Lack of TNFRI enhances ovarian responsiveness to gonadotropins during the prepubertal period, potentially contributing to early vaginal opening.
- TNFRI plays a critical role in regulating female reproductive function, with its absence leading to impaired fertility and early aging.
- The findings demonstrate that TNFRI is the primary mediator of TNF-induced inhibition of steroidogenesis.