Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran.
Department of Physiology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran; Neurophysiology Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran.
J Trace Elem Med Biol. 2021 Sep;67:126776. doi: 10.1016/j.jtemb.2021.126776. Epub 2021 May 8.
Chronic use of morphine is associated with reproductive complications, such as hypogonadism and infertility. While the side effects of morphine have been extensively studied in the testis, much less is known regarding the effects of morphine on Sertoli cells and the effects of zinc on morphine-induced testicular injury as well as their underlying mechanisms. Therefore, the purpose of this study was to investigate the effect of morphine (alone and co-administered with zinc) on cell viability and apoptosis of the testicular (Sertoli) cells as well as the tumor suppressor p53 and phosphorylated-protein kinase B (p-Akt) protein levels in both in vitro and in vivo models.
Cultured Sertoli cells were exposed to morphine (23 μM), zinc (8 μM), and zinc prior to morphine and their effects on Sertoli cell viability and apoptosis were investigated. Morphine (3 mg/kg) and zinc (5 mg/kg, 1 h before morphine) were also injected intraperitoneally to rats and then the apoptotic changes in the testis were evaluated.
Cell viability and p-Akt protein levels decreased in morphine-treated cells, while apoptosis and p53 protein expression increased in these cells. Pretreatment with zinc recovered morphine-induced apoptotic effects, as well as over-expression of p53 and down-regulation of p-Akt. These findings were supported by a subsequent animal study.
The present data indicated the protective effect of zinc against morphine-induced testicular (Sertoli) cell toxicity via p53/Akt pathways in both in vivo and in vitro models and suggested the clinical importance of zinc on infertility among chronic opioid users and addicted men.
慢性使用吗啡会导致生殖并发症，如性腺功能减退和不育。虽然吗啡的副作用在睾丸中已经得到了广泛研究，但对于吗啡对支持细胞的影响以及锌对吗啡诱导的睾丸损伤及其潜在机制的影响知之甚少。因此，本研究的目的是研究吗啡（单独使用和与锌联合使用）对体外和体内模型中睾丸（支持细胞）细胞活力和凋亡以及肿瘤抑制因子 p53 和磷酸化蛋白激酶 B（p-Akt）蛋白水平的影响。
培养的支持细胞暴露于吗啡（23 μM）、锌（8 μM）和锌之前吗啡，研究其对支持细胞活力和凋亡的影响。吗啡（3 mg/kg）和锌（5 mg/kg，在吗啡前 1 小时）也被腹膜内注射到大鼠中，然后评估睾丸中的凋亡变化。
吗啡处理的细胞中细胞活力和 p-Akt 蛋白水平下降，而这些细胞中的细胞凋亡和 p53 蛋白表达增加。锌预处理恢复了吗啡诱导的凋亡作用，以及 p53 的过度表达和 p-Akt 的下调。这些发现得到了随后的动物研究的支持。
本研究数据表明，锌通过 p53/Akt 通路在体内和体外模型中对吗啡诱导的睾丸（支持细胞）细胞毒性具有保护作用，并提示锌对慢性阿片类药物使用者和成瘾男性不育症的临床重要性。
