Li Weiwei, Yin Xiurong, Zhang Lei
Department of Reproductive Medicine, Qinhuangdao Maternal and Child Health Hospital, Qinhuangdao, China.
Department of Reproductive Medicine, Qinhuangdao Maternal and Child Health Hospital, Qinhuangdao, China.
Exp Cell Res. 2025 Jan 15;444(2):114388. doi: 10.1016/j.yexcr.2024.114388. Epub 2024 Dec 18.
Hypoxia-caused spermatogenesis impairment may contribute to male infertility. FOXA2 has been found to be abundant in spermatogonial stem cells and critical for spermatogenesis. Here we aimed to explore the roles of FOXA2 in regulating spermatogonial cells against hypoxia stimulation. Our results showed that FOXA2 expression was downregulated in hypoxia-stimulated spermatogonial cells. Overexpression of FOXA2 prevented hypoxia-induced endoplasmic reticulum (ER) stress with decreased expression levels of associated markers including GRP78, CHOP, and ATF-4. FOXA2 overexpression caused a decrease in MDA content and an increase in activities of SOD, CAT, and GSH-Px in spermatogonial cells under hypoxic conditions, implying its inhibitory effect on oxidative stress. Besides, cell apoptosis under hypoxic conditions was also prevented by FOXA2 overexpression, as shown by reduced apoptotic rate and caspase-3 activity. Moreover, we found that hypoxia stimulation inactivated the Nrf2 pathway, which could be prevented by FOXA2 overexpression. Nrf2 knockdown attenuated the effects of FOXA2 overexpression on hypoxia-induced ER stress, oxidative stress, and apoptosis in spermatogonial cells. In conclusion, FOXA2 exerted protective effects on spermatogonial cells against hypoxia-induced ER stress, oxidative stress, and apoptosis via regulating Nrf2/HO-1 signaling. These findings suggested that FOXA2 might be a therapeutic target for treating hypoxia-induced spermatogenesis impairment.
缺氧导致的生精障碍可能是男性不育的原因之一。FOXA2在精原干细胞中大量表达，对精子发生至关重要。本研究旨在探讨FOXA2在调节精原细胞抵抗缺氧刺激中的作用。结果显示，缺氧刺激下精原细胞中FOXA2表达下调。过表达FOXA2可减轻缺氧诱导的内质网（ER）应激，GRP78、CHOP和ATF-4等相关标志物的表达水平降低。过表达FOXA2可使缺氧条件下精原细胞中丙二醛（MDA）含量降低，超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽过氧化物酶（GSH-Px）活性升高，提示其对氧化应激具有抑制作用。此外，过表达FOXA2还可抑制缺氧条件下的细胞凋亡，表现为凋亡率和半胱天冬酶-3（caspase-3）活性降低。此外，我们发现缺氧刺激会使核因子E2相关因子2（Nrf2）信号通路失活，而过表达FOXA2可防止这种情况发生。敲低Nrf2可减弱FOXA2过表达对缺氧诱导的精原细胞内质网应激、氧化应激和凋亡的影响。总之，FOXA2通过调节Nrf2/血红素加氧酶-1（HO-1）信号通路，对精原细胞缺氧诱导的内质网应激、氧化应激和凋亡发挥保护作用。这些发现提示FOXA2可能是治疗缺氧诱导的生精障碍的治疗靶点。
