Ommati Mohammad Mehdi, Arabnezhad Mohammad Reza, Farshad Omid, Jamshidzadeh Akram, Niknahad Hossein, Retana-Marquez Socorro, Jia Zhipeng, Nateghahmadi Mohammad Hassan, Mousavi Khadijeh, Arazi Aysooda, Azmoon Mohammad Reza, Azarpira Negar, Heidari Reza
Department of Bioinformatics, College of Life Sciences, Shanxi Agricultural University, Taigu, China.
Department of Toxicology and Pharmacology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.
Front Vet Sci. 2021 Mar 24;8:603262. doi: 10.3389/fvets.2021.603262. eCollection 2021.
Lithium (Li) is prescribed against a wide range of neurological disorders. Besides its excellent therapeutic properties, there are several adverse effects associated with Li. The impact of Li on renal function and diabetes insipidus is the most common adverse effect of this drug. On the other hand, infertility and decreased libido is another complication associated with Li. It has been found that sperm indices of functionality, as well as libido, is significantly reduced in Li-treated men. These adverse effects might lead to drug incompliance and the cessation of drug therapy. Hence, the main aims of the current study were to illustrate the mechanisms of adverse effects of Li on the testis tissue, spermatogenesis process, and hormonal changes in two experimental models. In the experiments, Leydig cells (LCs) were isolated from healthy mice, cultured, and exposed to increasing concentrations of Li (0, 10, 50, and 100 ppm). In the section of the current study, mice were treated with Li (0, 10, 50, and 100 ppm, in drinking water) for five consecutive weeks. Testis and sperm samples were collected and assessed. A significant sign of cytotoxicity (LDH release and MTT assay), along with disrupted testosterone biosynthesis, impaired mitochondrial indices (ATP level and mitochondrial depolarization), and increased biomarkers of oxidative stress were detected in LCs exposed to Li. On the other hand, a significant increase in serum and testis Li levels were detected in drug-treated mice. Moreover, ROS formation, LPO, protein carbonylation, and increased oxidized glutathione (GSSG) were detected in both testis tissue and sperm specimens of Li-treated mice. Several sperm anomalies were also detected in Li-treated animals. On the other hand, sperm mitochondrial indices (mitochondrial dehydrogenases activity and ATP levels) were significantly decreased in drug-treated groups where mitochondrial depolarization was increased dose-dependently. Altogether, these data mention oxidative stress and mitochondrial impairment as pivotal mechanisms involved in Li-induced reproductive toxicity. Therefore, based on our previous publications in this area, therapeutic options, including compounds with high antioxidant properties that target these points might find a clinical value in ameliorating Li-induced adverse effects on the male reproductive system.
锂（Li）被用于治疗多种神经系统疾病。除了其出色的治疗特性外，锂还存在一些不良反应。锂对肾功能和尿崩症的影响是这种药物最常见的不良反应。另一方面，不育和性欲减退是与锂相关的另一种并发症。研究发现，接受锂治疗的男性精子功能指标以及性欲显著降低。这些不良反应可能导致药物依从性降低和药物治疗中断。因此，本研究的主要目的是阐明锂在两个实验模型中对睾丸组织、精子发生过程和激素变化产生不良反应的机制。在实验中，从健康小鼠中分离出睾丸间质细胞（LCs），进行培养，并使其暴露于浓度不断增加的锂（0、10、50和100 ppm）中。在本研究的另一部分中，小鼠连续五周饮用含锂（0、10、50和100 ppm）的水进行处理。收集并评估睾丸和精子样本。在暴露于锂的睾丸间质细胞中检测到细胞毒性的显著迹象（乳酸脱氢酶释放和MTT测定），同时伴有睾酮生物合成紊乱、线粒体指标受损（ATP水平和线粒体去极化）以及氧化应激生物标志物增加。另一方面，在接受药物治疗的小鼠中检测到血清和睾丸锂水平显著升高。此外，在接受锂治疗的小鼠的睾丸组织和精子样本中均检测到活性氧形成、脂质过氧化、蛋白质羰基化以及氧化型谷胱甘肽（GSSG）增加。在接受锂治疗的动物中还检测到几种精子异常情况。另一方面，在药物治疗组中，精子线粒体指标（线粒体脱氢酶活性和ATP水平）显著降低，且线粒体去极化呈剂量依赖性增加。总之，这些数据表明氧化应激和线粒体损伤是锂诱导生殖毒性的关键机制。因此，基于我们之前在该领域的出版物，包括具有高抗氧化特性且针对这些靶点的化合物在内的治疗选择，可能在改善锂对男性生殖系统的不良反应方面具有临床价值。
