Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, China; General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, China.
Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
Cell Signal. 2024 Oct;122:111334. doi: 10.1016/j.cellsig.2024.111334. Epub 2024 Aug 3.
Chronic psychological stress is associated with impaired follicular development and ovarian dysfunction. Many aspects of this dysfunction and the underlying mechanisms remain unclear. Using a chronic unpredictable mild stress (CUMS) mouse model, we investigate the influence of chronic stress on ovarian function and explore potential mechanisms.
A CUMS mouse model was constructed over eight months, covering the period from sexual maturity to the onset of declining fertility in mice. At the end of the 2nd, 4th, 6th, and 8th months of exposure to CUMS, behavioral and physiological assays, including the sucrose preference test, tail suspension test, and serum corticosterone levels, were conducted to validate the effectiveness of the stress model. Fertility and ovarian function were assessed by analyzing the estrous cycle, number of offspring, sex hormone levels, follicle counts, granulosa cell proliferation and apoptosis, and the expression levels of fibrosis markers. Furthermore, proteomic analyses were performed on the ovaries to investigate the molecular mechanisms of ovarian fibrosis induced by CUMS.
With continued CUMS exposure, there was a gradual decline in both the ovary-to-body weight ratio and the number of offspring. Moreover, the percentage of atretic follicles was notably higher in the CUMS-exposed groups compared to the control groups. It is noticeable that CUMS triggered granulosa cell apoptosis and halted proliferation. Additionally, increased expression of α-SMA and Collagen I in the ovaries of CUMS-exposed mice indicated that CUMS could induce ovarian fibrosis. Proteomic analysis provided insights into the activation of specific biological processes and molecules associated with fibrosis induced by chronic stress.
Our results strongly suggest that exposure to CUMS induces ovarian fibrosis, which influences follicular development and ultimately contributes to fertility decline. These findings offer novel perspectives on the impact of chronic stress on ovarian dysfunction.
慢性心理应激与卵泡发育受损和卵巢功能障碍有关。这种功能障碍的许多方面及其潜在机制仍不清楚。本研究使用慢性不可预测轻度应激（CUMS）小鼠模型，研究慢性应激对卵巢功能的影响，并探讨潜在的机制。
建立了一个长达八个月的 CUMS 小鼠模型，涵盖了从性成熟到小鼠生育力下降开始的时期。在暴露于 CUMS 的第 2、4、6 和 8 个月结束时，进行行为和生理测定，包括蔗糖偏好试验、悬尾试验和血清皮质酮水平，以验证应激模型的有效性。通过分析发情周期、后代数量、性激素水平、卵泡计数、颗粒细胞增殖和凋亡以及纤维化标志物的表达水平来评估生育力和卵巢功能。此外，对卵巢进行蛋白质组学分析，以研究 CUMS 诱导卵巢纤维化的分子机制。
随着 CUMS 暴露的持续进行，卵巢与体重的比值和后代数量逐渐下降。此外，与对照组相比，CUMS 暴露组的闭锁卵泡百分比明显更高。值得注意的是，CUMS 引发了颗粒细胞凋亡并阻止了增殖。此外，CUMS 暴露小鼠卵巢中α-SMA 和 Collagen I 的表达增加表明 CUMS 可诱导卵巢纤维化。蛋白质组学分析提供了有关与慢性应激诱导的纤维化相关的特定生物学过程和分子激活的见解。
我们的结果强烈表明，暴露于 CUMS 会引起卵巢纤维化，这会影响卵泡发育并最终导致生育力下降。这些发现为慢性应激对卵巢功能障碍的影响提供了新的视角。
