背景:男性不育症的管理继续遇到一系列挑战和限制,需要深入探索新的治疗靶点以提高其疗效。作为一种八碳中链脂肪酸,辛酸(OCA)显示出改善健康的希望,然而,它对精子发生的影响仍未得到充分研究。
方法:进行质谱测定,以确定严重精子发生障碍患者血清中的脂肪酸含量和关键脂质成分。检查了精子质量,进行了组织病理学分析和生物素示踪试验,以评估体内生精功能和血睾丸屏障(BTB)的完整性。进行了基于细胞的体外实验以研究OCA给药对支持细胞功能障碍的影响。本研究旨在阐明OCA可能影响支持细胞功能的机制。
结果:严重精子发生障碍患者血清中OCA含量显著降低,表明OCA缺乏与生精障碍有关。在白消安以30mg/kg体重(BW)的剂量诱导的生精障碍小鼠模型中测试了OCA对生殖的保护作用。研究中的小鼠被分成不同的组,并给予不同量的OCA,特别是在32、64、128和256mg/kgBW的剂量下。在评估精子参数后,最有效剂量为32mg/kg体重。体内实验表明,用OCA治疗可显着提高精子质量,睾丸组织病理学和BTB完整性,被白消安损坏了。此外,OCA干预降低白消安诱导的小鼠睾丸氧化应激和自噬。体外,OCA预处理(100µM)通过减轻白消安(800µM)诱导的氧化应激和自噬显着改善了支持细胞功能障碍。此外,雷帕霉素(5µM)诱导的自噬导致支持细胞屏障功能障碍,而OCA给药通过减轻自噬发挥保护作用。
结论:本研究表明,OCA可以抑制氧化应激和自噬,从而减轻白消安诱导的BTB损伤。这些发现为白消安的毒理学提供了更深入的了解,并为开发基于OCA的新型男性不育疗法提供了有希望的途径。
BACKGROUND: The management of male infertility continues to encounter an array of challenges and constraints, necessitating an in-depth exploration of novel therapeutic targets to enhance its efficacy. As an eight-carbon medium-chain fatty acid, octanoic acid (OCA) shows promise for improving health, yet its impact on spermatogenesis remains inadequately researched.
METHODS: Mass spectrometry was performed to determine the fatty acid content and screen for a pivotal lipid component in the serum of patients with severe spermatogenesis disorders. The sperm quality was examined, and histopathological analysis and biotin tracer tests were performed to assess spermatogenesis function and the integrity of the blood-testis barrier (BTB) in vivo. Cell-based in vitro experiments were carried out to investigate the effects of OCA administration on Sertoli cell dysfunction. This research aimed to elucidate the mechanism by which OCA may influence the function of Sertoli cells.
RESULTS: A pronounced reduction in OCA content was observed in the serum of patients with severe spermatogenesis disorders, indicating that OCA deficiency is related to spermatogenic disorders. The protective effect of OCA on reproduction was tested in a mouse model of spermatogenic disorder induced by
busulfan at a dose 30 mg/kg body weight (BW). The mice in the study were separated into distinct groups and administered varying amounts of OCA, specifically at doses of 32, 64, 128, and 256 mg/kg BW. After evaluating sperm parameters, the most effective dose was determined to be 32 mg/kg BW. In vivo experiments showed that treatment with OCA significantly improved sperm quality, testicular histopathology and BTB integrity, which were damaged by
busulfan. Moreover, OCA intervention reduced
busulfan-induced oxidative stress and autophagy in mouse testes. In vitro, OCA pretreatment (100 µM) significantly ameliorated Sertoli cell dysfunction by alleviating
busulfan (800 µM)-induced oxidative stress and autophagy. Moreover, rapamycin (5 µM)-induced autophagy led to Sertoli cell barrier dysfunction, while OCA administration exerted a protective effect by alleviating autophagy.
CONCLUSIONS: This study demonstrated that OCA administration suppressed oxidative stress and autophagy to alleviate busulfan-induced BTB damage. These findings provide a deeper understanding of the toxicology of
busulfan and a promising avenue for the development of novel OCA-based therapies for male infertility.