Repeated oral administration of low doses of silver in mice: tissue distribution and effects on central nervous system

Abstract

Background 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. Results 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. Conclusions 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.

Coating-Dependent Neurotoxicity of Silver Nanoparticles—An In Vivo Study on Hippocampal Oxidative Stress and Neurosteroids

“…This extensive usage of AgNPs and their proven ability to cross biological barriers, such as the blood-brain barrier, have raised concerns about their potential influence on brain functions. Results obtained by Recordati et al showed high deposition of silver in the brain after oral exposure of environmentally relevant dose of citrate-coated AgNPs at the end of the administration as well as after 4 weeks of recovery that highlighted slow elimination of Ag from the brain structures [23]. Our previous study has also shown that oral administration of AgNPs at a relatively small concentration resulted in a time-dependent accumulation of silver in the brain, particularly in the hippocampus, and simultaneous deterioration of learning skills in rats [16,24].…”

Therapeutic Applications of Antimicrobial Silver-Based Biomaterials in Dentistry

“… 44–46 Recordati et al observed slow clearance of silver and ultrastructural changes of the blood-brain barrier after oral administration of 1 mg/kg AgNPs and silver acetate in mice, without any treatment-related signs or effects on body and organ weights. 47 …”

Accumulation and Effect of Silver Nanoparticles Functionalized with Spirulina platensis on Rats

“…The amount of silver that remained in the brain was approximately equal for both types of nanoparticles. Other authors have also established the persistence of silver accumulated in the brain even after a period of clearance, highlighting its slow elimination from this organ [31].…”