School of Public Health, MOE Key Laboratory for Public Health Safety, Key Laboratory of Health Technology Assessment of National Health Commission, Fudan University, Shanghai 200032, China.
School of Public Health, MOE Key Laboratory for Public Health Safety, Key Laboratory of Health Technology Assessment of National Health Commission, Fudan University, Shanghai 200032, China; Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai 201203, China.
Toxicol Lett. 2018 Oct 1;295:277-287. doi: 10.1016/j.toxlet.2018.07.001. Epub 2018 Jul 5.
There are reports of fluorochloridone (FLC)-induced male reproductive toxicity, but the underlying toxicological mechanisms remain unknown. In this study, we looked at how FLC exposure affected the integrity of the blood-testis barrier (BTB) and the Sertoli cell barrier and studied the molecular mechanisms. Male rats received gavage administration of FLC (30 mg/kg/d) for 14 consecutive days with sample collection at the 7th and 14th day; and primary cultured Sertoli cells were treated with 0-10 μM FLC in vitro for 24 h. Our in vivo findings revealed that FLC exposure caused time-dependent testicular injuries, sperm quality decrease as well as adverse changes in BTB integrity, F-actin organization, and expressions of claudin-11 and Arp3. In Sertoli cells isolated from FLC-treated rat testis, Sertoli cell barrier tightness was increased. In Sertoli cells in vitro exposed to FLC, abnormal changes in the barrier permeability were also observed, and the protein expressions of occludin, claudin-11, ZO-1, connexin-43, and Arp3 were significantly decreased in a dose- and time-dependent manner. Furthermore, the FLC-induced adverse changes in Sertoli cell barrier and F-actin were partly alleviated by the induction of Arp3 overexpression. In conclusion, our findings revealed that FLC perturbed BTB/Sertoli cell barrier function through Arp3-mediated F-actin disorganization.
有报道称氟氯西林（FLC）可导致雄性生殖毒性，但潜在的毒理学机制尚不清楚。在这项研究中，我们研究了 FLC 暴露如何影响血睾屏障（BTB）和支持细胞屏障的完整性，并研究了其分子机制。雄性大鼠连续 14 天经灌胃给予 FLC（30mg/kg/d），在第 7 天和第 14 天收集样本；体外将原代培养的支持细胞用 0-10μM FLC 处理 24h。我们的体内研究结果表明，FLC 暴露可导致睾丸损伤、精子质量下降以及 BTB 完整性、F-肌动蛋白组织和 claudin-11、Arp3 表达的时间依赖性改变。在 FLC 处理的大鼠睾丸支持细胞中，支持细胞屏障的紧密性增加。在体外暴露于 FLC 的支持细胞中，也观察到了屏障通透性的异常变化，occludin、claudin-11、ZO-1、connexin-43 和 Arp3 的蛋白表达呈剂量和时间依赖性显著降低。此外，Arp3 过表达可部分缓解 FLC 诱导的支持细胞屏障和 F-肌动蛋白的不良变化。总之，我们的研究结果表明，FLC 通过 Arp3 介导的 F-肌动蛋白解聚破坏了 BTB/支持细胞屏障功能。
