Widespread use of silver in its different forms raises concerns about potential adverse effects after ingestion, the main exposure route for humans. The aim of this study was to investigate in CD-1 (ICR) male mice the tissue distribution and in vivo effects of 4-week oral exposure to 0.25 and 1 mg Ag/kg bw 10 nm citrate coated silver nanoparticles (AgNPs) and 1 mg Ag/kg bw silver acetate (AgAc) at the end of treatment (EoT) and after 4 weeks of recovery. There were no treatment-related clinical signs and mortality, and no significant effects on body and organ weights at the EoT and after recovery. Treatment-related changes in hematology and clinical chemistry were found after recovery, the most relevant being a dose-dependent lymphopenia and increased triglycerides in AgNP-treated mice, and increased levels of urea in all treated groups, associated with decreased albumin only in AgAc-treated mice. At the EoT the highest silver concentration determined by Triple Quadrupole ICP-MS analysis was found in the brain, followed by testis, liver, and spleen; much lower concentrations were present in the small intestine and kidney. Tissue silver concentrations were slightly higher after exposure to AgAc than AgNPs and dose dependent for AgNPs. After recovery silver was still present in the brain and testis, highlighting slow elimination. No histopathological changes and absence of silver staining by autometallography were observed in the organs of treated mice. At the EoT GFAP (astrocytes) immunoreactivity was significantly increased in the hippocampus of AgNP-treated mice in a dose-dependent manner and Iba1 (microglial cells) immunoreactivity was significantly increased in the cortex of 1 mg/kg bw AgNP-treated mice. After recovery, a significant reduction of Iba1 was observed in the cortex of all treated groups. TEM analysis of the hippocampus revealed splitting of basement membrane of the capillaries and swelling of astrocytic perivascular end-feet in 1 mg/kg bw AgNP- and AgAc-treated mice at the EoT. Our study revealed accumulation and slow clearance of silver in the brain after oral administration of 10 nm AgNPs and AgAc at low doses in mice, associated with effects on glial cells and ultrastructural alterations of the Blood-Brain Barrier.

中文翻译：

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小鼠反复口服低剂量银：组织分布及对中枢神经系统的影响

广泛使用不同形式的银引起了人们对摄入后潜在不良影响的担忧，这是人类的主要接触途径。本研究的目的是在 CD-1 (ICR) 雄性小鼠中研究 4 周口服暴露于 0.25 和 1 mg Ag/kg bw 10 nm 柠檬酸盐涂层银纳米粒子 (AgNPs) 和 1在治疗结束 (EoT) 和恢复 4 周后，mg Ag/kg bw 醋酸银 (AgAc)。没有与治疗相关的临床症状和死亡率，并且在 EoT 和恢复后对体重和器官重量没有显着影响。恢复后发现与治疗相关的血液学和临床化学变化，最相关的是剂量依赖性淋巴细胞减少症和 AgNP 治疗小鼠的甘油三酯增加，以及所有治疗组的尿素水平增加，仅在 AgAc 治疗的小鼠中与白蛋白降低有关。在 EoT 时，通过三重四极杆 ICP-MS 分析确定的最高银浓度出现在大脑中，其次是睾丸、肝脏和脾脏；小肠和肾脏中的浓度要低得多。暴露于 AgAc 后，组织银浓度略高于 AgNPs，并且 AgNPs 的剂量依赖性。恢复后，大脑和睾丸中仍存在银，表明消除缓慢。在处理过的小鼠的器官中没有观察到组织病理学变化和自体金相学显示没有银染色。在 EoT GFAP（星形胶质细胞）免疫反应性在 AgNP 治疗小鼠的海马体中以剂量依赖性方式显着增加，而 Iba1（小胶质细胞）免疫反应性在 1 mg/kg bw AgNP 治疗小鼠的皮层中显着增加。恢复后，在所有治疗组的皮质中观察到 Iba1 显着减少。海马的 TEM 分析显示，在 EoT 时，1 mg/kg bw AgNP 和 AgAc 处理的小鼠的毛细血管基底膜分裂和星形胶质细胞血管周围末端肿胀。我们的研究揭示了在小鼠中口服低剂量 10 nm AgNPs 和 AgAc 后，银在大脑中的积累和缓慢清除，这与对神经胶质细胞的影响和血脑屏障的超微结构改变有关。在所有治疗组的皮质中观察到 Iba1 的显着减少。海马的 TEM 分析显示，在 EoT 时，1 mg/kg bw AgNP 和 AgAc 处理的小鼠的毛细血管基底膜分裂和星形胶质细胞血管周围末端肿胀。我们的研究揭示了在小鼠中口服低剂量 10 nm AgNPs 和 AgAc 后，银在大脑中的积累和缓慢清除，这与对神经胶质细胞的影响和血脑屏障的超微结构改变有关。在所有治疗组的皮质中观察到 Iba1 的显着减少。海马的 TEM 分析显示，在 EoT 时，1 mg/kg bw AgNP 和 AgAc 处理的小鼠的毛细血管基底膜分裂和星形胶质细胞血管周围末端肿胀。我们的研究揭示了在小鼠中口服低剂量 10 nm AgNPs 和 AgAc 后，银在大脑中的积累和缓慢清除，这与对神经胶质细胞的影响和血脑屏障的超微结构改变有关。