College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi Province, 712100, PR China.
Xining Animal Disease Prevention and Control Center, Xining, Qinghai Province, 810003, PR China.
Toxicology. 2021 May 15;455:152749. doi: 10.1016/j.tox.2021.152749. Epub 2021 Mar 23.
Isoniazid (INH), a synthetic first-line tuberculosis antibiotic, has been widely used in clinical treatment. It has been reported to cause toxic effects at multiple tissue sites and also increases the incidence of adverse pregnancy outcomes; but the mechanism of action of INH on the reproductive system of female mammals remains unclear. Here, we demonstrate that oral INH (40 mg/kg/day every other day for 28 days) severely affects oocyte maturation and fertilization, late blastocyst development and fertility. We found that INH could disrupt standard spindle assembly, chromosome arrangement, and actin filament dynamics, which compromised meiotic progression of mouse oocytes. INH treatment increased the level of reactive oxygen species (ROS) and activated the oxidative stress response pathway, Keap1-Nrf2. It also caused apoptosis of oocytes and mitochondrial dysfunction. Our findings demonstrate that oral INH reduces fertility and damages the mammalian reproductive system by altering cytoskeletal dynamics and Juno expression, inducing oxidative stress and apoptosis, and activating the Keap1-Nrf2 signaling pathway in mouse oocytes.
异烟肼（INH），一种合成的一线抗结核抗生素，已广泛用于临床治疗。据报道，它会在多个组织部位引起毒性作用，还会增加不良妊娠结局的发生率；但 INH 对雌性哺乳动物生殖系统的作用机制尚不清楚。在这里，我们证明口服 INH（每天 40mg/kg，每隔一天一次，共 28 天）会严重影响卵母细胞成熟和受精、晚期囊胚发育和生育能力。我们发现 INH 可以破坏标准纺锤体的组装、染色体排列和肌动蛋白丝动力学，从而影响卵母细胞的减数分裂进程。INH 处理会增加活性氧（ROS）的水平并激活氧化应激反应途径 Keap1-Nrf2。它还会导致卵母细胞凋亡和线粒体功能障碍。我们的研究结果表明，口服 INH 通过改变细胞骨架动力学和 Juno 表达、诱导氧化应激和细胞凋亡以及激活 Keap1-Nrf2 信号通路，降低生育能力并损害哺乳动物的生殖系统，在小鼠卵母细胞中。
