Department of Urology and Nephrology, The Third Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Physiol Res. 2020 Apr 30;69(2):297-306. doi: 10.33549/physiolres.934287. Epub 2020 Mar 23.
Chronic stress is a crucial public issue that occurs when a person is repetitively stimulated by various stressors. Previous researches have reported that chronic stress induces spermatogenesis dysfunction in the reproductive system, but its molecular mechanisms remain unclear. The nectin protein family, including nectin-1 to nectin-4, is Ca(2+)-independent immunoglobulin-like cell adhesion molecules, that are widely expressed in the hippocampus, testicular tissue, epithelial cells and other sites. Nectin-3 contributes to the sperm development at the late stage, and the abnormal expression of nectin-3 impairs spermatogenesis. Some recent studies have demonstrated that stress induces a decrease in nectin-3 expression in the hippocampus via corticotropin-releasing hormone (CRH) to corticotropin-releasing hormone receptor 1 (CRHR1) pathway. Here, we tested whether chronic stress also caused a reduction in nectin-3 expression in the testis. We established a chronic social defeat stress paradigm, which provides naturalistic and complex chronic stress inmale C57BL/6 mice. After 25 days of chronic social defeat stress, the mice showed weight loss, thymic atrophy and some other typical symptoms of chronic stress (e.g.anxiety-like behavior and social avoidance behavior). We found gonad atrophy, testicular histological structure changes and semen quality reductions in the stressed mice. The stressed male mice significantly spent more time to impregnate the female mice than the control male mice. Moreover, nectin-3 protein levels in stressed mice were significantly decreased in the testes compared with those in control mice. In addition, we found that the CRHR1 expression level was increased in the testes of stressed mice. Therefore, we demonstrated a decreased level of nectin-3 expression and an increase in CRHR1 expression in the testis after exposure to chronic stress, which may provide a potential therapeutic target for the spermatogenesis dysfunction induced by chronic stress.
慢性应激是指当一个人反复受到各种应激源刺激时发生的一个重要公共问题。先前的研究报告表明，慢性应激会导致生殖系统中的精子发生功能障碍，但其分子机制尚不清楚。黏附蛋白家族包括 nectin-1 到 nectin-4，是 Ca(2+) 非依赖性免疫球蛋白样细胞黏附分子，广泛表达于海马体、睾丸组织、上皮细胞等部位。 nectin-3 有助于精子在晚期的发育，而 nectin-3 的异常表达会损害精子发生。一些最近的研究表明，应激通过促肾上腺皮质激素释放激素 (CRH) 到促肾上腺皮质激素释放激素受体 1 (CRHR1) 途径诱导海马体中 nectin-3 表达减少。在这里，我们测试了慢性应激是否也会导致睾丸中 nectin-3 表达减少。我们建立了慢性社会挫败应激模型，该模型为雄性 C57BL/6 小鼠提供了自然和复杂的慢性应激。经过 25 天的慢性社会挫败应激后，小鼠出现体重减轻、胸腺萎缩和其他一些慢性应激的典型症状（如焦虑样行为和社会回避行为）。我们发现应激小鼠的性腺萎缩、睾丸组织结构改变和精液质量下降。应激雄性小鼠使雌性小鼠受孕的时间明显长于对照雄性小鼠。此外，与对照小鼠相比，应激小鼠睾丸中的 nectin-3 蛋白水平显著降低。此外，我们发现应激小鼠睾丸中的 CRHR1 表达水平增加。因此，我们证明了慢性应激后睾丸中 nectin-3 表达水平降低和 CRHR1 表达增加，这可能为慢性应激引起的精子发生功能障碍提供了一个潜在的治疗靶点。
