阻断t型钙通道会破坏体内精子发生,并通过损害线粒体功能和自噬通量对体外精母细胞产生不利影响。

IF 2.8 4区 医学 Q2 REPRODUCTIVE BIOLOGY
Xiuling Zhao , Lei Wang , Shiqin Huang , Lin Liu , Xiaorong Wang , Liping Pu , Hao Chen , Junyu Nie
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引用次数: 0

摘要

t型钙通道在精子发生中起关键作用。为了研究t型钙通道调控精子发生的分子机制,我们使用t型钙通道抑制剂氟桂利嗪(FNZ)构建了动物和细胞模型。腹腔注射FNZ (30mg/kg)显著损害雄性小鼠精子活力,抑制睾丸生殖细胞增殖,破坏精子线粒体功能。在7.5μM、15μM和30μM浓度下,FNZ显著抑制小鼠精母细胞(GC-2)的增殖。FNZ的有害影响是通过破坏钙稳态、线粒体功能障碍和诱导细胞凋亡介导的。此外,FNZ暴露导致自噬体的积累和P62蛋白的上调,这与自噬降解有关。值得注意的是,自噬激活剂雷帕霉素(Rapamycin, Rapa)通过增强自噬过程来减轻fnz诱导的GC-2细胞损伤。相反,一种破坏溶酶体降解的自噬抑制剂氯喹(CQ)证实了FNZ在自噬调节中的作用。我们的研究结果表明,FNZ诱导线粒体损伤,损害精子活力和精子细胞增殖,并伴有自噬通量障碍。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Blocking T-type calcium channels disrupts spermatogenesis in vivo and adversely affects spermatocytes in vitro by impairing mitochondrial function and autophagic flux
T-type calcium channels are pivotal in spermatogenesis. To evaluate the molecular mechanisms by which T-type calcium channels regulate spermatogenesis, we constructed animal and cellular models using T-type calcium channel inhibitor flunarizine (FNZ). Intraperitoneal administration of FNZ (30 mg/kg) significantly impaired sperm motility, inhibited testicular germ cell proliferation, and disrupted sperm mitochondrial function in male mice. FNZ, at concentrations of 7.5 μM, 15 μM, and 30 μM, significantly inhibited mouse spermatocyte (GC-2) cells proliferation. The detrimental effects of FNZ were mediated through the disruption of calcium homeostasis, mitochondrial dysfunction, and the induction of apoptosis. Moreover, FNZ exposure resulted in the accumulation of autophagosomes and an upregulation of P62 protein, which is implicated in autophagic degradation. Notably, the autophagy activator Rapamycin (Rapa) was found to mitigate FNZ-induced cellular damage in GC-2 cells by enhancing autophagy process. Conversely, chloroquine (CQ), an autophagy inhibitor that disrupts lysosomal degradation, corroborated the role of FNZ in autophagy modulation. Our results indicate that FNZ induces mitochondrial damage, impairs sperm motility and spermatocyte proliferation, and is accompanied by obstacles to autophagic flux.
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来源期刊
Reproductive toxicology
Reproductive toxicology 生物-毒理学
CiteScore
6.50
自引率
3.00%
发文量
131
审稿时长
45 days
期刊介绍: Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.
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