Mapping a sustainable approach with whey-biosynthesized silver nanocomposites versus chemically synthesized silver nanoparticles in a chronic hippocampal toxicity rat model

Silver nanoparticles (AgNPs) are increasingly utilized in food-contact materials and dairy processing systems. However, the chronic oral effects of these materials have not been sufficiently characterized. This study compared hippocampal responses to chemically synthesized AgNPs (8–11 nm) suspended in whey-based medium (WBM) at measured silver concentrations with those from biogenic silver nanocomposites (AgNCs; 13.3 ± 3.6 nm). These were administered orally to male Sprague–Dawley rats (120–150 g, n = 5 per group) for 90 days. AgNCs were biosynthesized by fermenting WBM with Lactobacillus acidophilus using 4 mM or 6 mM AgNO 3 precursors, yielding 0.431 mg/mL and 0.647 mg/mL silver, respectively, as confirmed by ICP–OES with 99.99% efficiency. Chemical AgNPs were matched accordingly. Treatments included saline control (nC), WBM (wC), fermented WBM (LwC), low-dose chAg4w/bioAg4Lw (4.31 mg/day, approximately 28.8 mg/kg/day), and high-dose chAg6w/bioAg6Lw (6.47 mg/day, approximately 43.1 mg/kg/day) via 10 mL daily oral gavage. Chemical AgNPs elevated hippocampal malondialdehyde (MDA) and nitric oxide (NO) levels, reduced glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione (GSH), and altered Nrf2/SOD/NF-κB/iNOS/caspase-3 expression. Transmission electron microscopy (TEM) confirmed mitochondrial swelling, chromatin condensation, and myelin unraveling. In contrast, biogenic AgNCs preserved redox/gene homeostasis and ultrastructure akin to controls. These findings demonstrate that chemical AgNPs induce oxidative, apoptotic, and myelin damage at realistic chronic oral doses, while whey/ L. acidophilus AgNCs provide a safer-by-design alternative for antimicrobial applications.