Yadav Shubhanshu, Yadav Anupam, Mishra Raghav Kumar
Male Reproductive Physiology Lab., Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
Male Reproductive Physiology Lab., Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India.
Reprod Toxicol. 2025 Mar;132:108845. doi: 10.1016/j.reprotox.2025.108845. Epub 2025 Jan 28.
The unpredictable nature of stress complicates understanding its relationship with male infertility. In this study, we investigated testicular germ cell and junctional dynamics in male mice following exposure to chronic unpredictable stress (CUS). Adult Parkes male mice were exposed to CUS for 35 days (one complete spermatogenic cycle), with a random stressor (restraint stress, water deprivation, food deprivation, light flashing, wet bedding, cage shaking, or cage tilting) applied once per day in an intermittent and unpredictable manner to avoid repeating the same stimulus on consecutive days. CUS exposure caused behavioral alterations in mice, as observed through the forced swim test and the tail suspension test. CUS inhibited testosterone biosynthesis by decreasing steroidogenic markers (SF-1, StAR, 3β-HSD, and 17β-HSD). It also resulted in altered oxido-inflammatory and apoptotic markers, including increased LPO, Caspase-3, IKKβ, and NF-κB, along with decreased Nrf2, HO-1, SOD, and catalase in the testis. CUS exposure reduced 1 C and 4 C germ cell populations and decreased germ cell ratios (1 C:2 C, 4 C:2 C, and 4 C:S-phase), impairing sperm development. CUS disrupted meiosis initiation, chromosomal synapsis, and germ cell maintenance by reducing Stra8, SYCP3, and Piwil1 expression in the testis. It also adversely affected blood-testis barrier markers, such as ZO-1 and connexin43. These changes led to altered testicular histomorphology, reduced daily sperm production, and disrupted germ cell dynamics. The findings suggest that CUS inhibits steroidogenesis and perturbs the Nrf2/HO-1/IKKβ/NF-κB oxido-inflammatory pathway. This leads to disrupted germ cell dynamics, compromised blood-testis barrier integrity, altered histomorphology, and reduced sperm production, collectively resulting in testicular dysfunction.
压力的不可预测性使得理解其与男性不育之间的关系变得复杂。在本研究中，我们调查了慢性不可预测应激（CUS）暴露后雄性小鼠睾丸生殖细胞和连接动态。成年帕克斯雄性小鼠暴露于CUS 35天（一个完整的生精周期），每天以间歇性和不可预测的方式施加一次随机应激源（束缚应激、禁水、禁食、闪光、湿垫料、摇晃笼子或倾斜笼子），以避免连续几天重复相同的刺激。通过强迫游泳试验和尾悬挂试验观察到，CUS暴露导致小鼠行为改变。CUS通过降低类固醇生成标志物（SF-1、StAR、3β-HSD和17β-HSD）来抑制睾酮生物合成。它还导致氧化炎症和凋亡标志物改变，包括睾丸中LPO、Caspase-3、IKKβ和NF-κB增加，以及Nrf2、HO-1、SOD和过氧化氢酶减少。CUS暴露减少了1C和4C生殖细胞群体，并降低了生殖细胞比例（1C:2C、4C:2C和4C:S期），损害了精子发育。CUS通过降低睾丸中Stra8、SYCP3和Piwil1的表达，破坏减数分裂起始、染色体联会和生殖细胞维持。它还对血睾屏障标志物如ZO-1和连接蛋白43产生不利影响。这些变化导致睾丸组织形态改变、每日精子产量减少和生殖细胞动态破坏。研究结果表明，CUS抑制类固醇生成并扰乱Nrf2/HO-1/IKKβ/NF-κB氧化炎症途径。这导致生殖细胞动态破坏、血睾屏障完整性受损、组织形态改变和精子产量减少，共同导致睾丸功能障碍。
