Dose-dependent neurotoxicity of starch-adorned silver nanoparticles: A chronic in vivo study

Silver nanoparticles (AgNPs) are widely used in various fields, including medicine, food products, water filtration systems, cosmetics, textiles, and packaging, due to their powerful antimicrobial activity. However, chronic exposure to AgNPs was found to pose risks to human health owing to their highly reactive surface, large surface area, and the potential to penetrate the blood brain barrier (BBB). In this study, the effects of chronic oral administration of AgNPs on the cognitive and behavioral functions of rats were investigated, and the molecular mechanisms underlying AgNPs-induced neurotoxicity were reported. Male Wistar adult rats were orally administered doses ranging from 10 μg/kg body weight (BW) to 10 mg/kg BW/day for 90 days. Results revealed that the effects of chronic oral administration of AgNPs were dose dependent. Spatial learning, memory, and locomotor activity in rats were impaired at doses above 500 μg/kg BW/day. Significant decline in the levels of brain neurotransmitters, including serotonin and acetylcholinesterase, was observed at doses above 100 μg/kg BW/day. However, a significant reduction in dopamine levels was observed to be between 10 and 100 μg/kg BW/day, indicating that dopaminergic pathways are highly sensitive to AgNPs exposure, even at minimal concentrations. Interesentingly, increase in oxidative stress markers (ROS, protein carbonylation and MDA) at doses above 100 μg/Kg BW/day, decrease in antioxidant potential (GSH and TAC) at dose of 10 μg/Kg BW/day, induction of DNA damage (8-OHdG), and apoptosis in the brain at doses above 100 μg/Kg BW/day were observed. Furthermore, H&E staining and immunohistochemical analysis of brain tissue revealed inflammation, apoptosis and alterations in brain architecture, with signs of degeneration observed at doses starting from 10 μg/kg BW/day. The presence of AgNPs was also detected in the cerebral cortex of animals receiving 2 and 5 mg/kg BW/day. The no-observed-adverse-effect level (NOAEL) for chronic administration of starch-coated AgNPs on brain health was determined to be 10 μg/kg BW/day, demonstrating that even low-dose, long-term exposure to AgNPs poses significant risks to the central nervous system.