Oral subchronic exposure to silver nanoparticles causes renal damage through apoptotic impairment and necrotic cell death

Abstract

Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials. Following oral exposure, AgNPs can accumulate in various organs including kidneys where they show gender specific accumulation. There is limited information on their effect on renal system following long-term animal exposure especially at the ultramicroscopic and molecular level. In this study, we have assessed the effect of 60 days oral AgNPs treatment on kidneys of female Wistar rats at doses of 50 ppm and 200 ppm that are below previously reported lowest observed adverse effect level (LOAEL). AgNPs treatment led to decrease in kidney weight and some loss of renal function as seen by increased levels of serum creatinine and early toxicity markers such as KIM-1, clusterin and osteopontin. We also observed significant mitochondrial damage, loss of brush border membranes, pronounced swelling of podocytes and degeneration of their foot processes using transmission electron microscopy (TEM). These symptoms are similar to those seen in nephrotic syndrome and 'Minimal change disease' of kidney where few changes are visible under light microscopy but significant ultrastructural damage is observed. Prolonged treatment of AgNPs also led to the activation of cell proliferative, survival and proinflammatory factors (Akt/mTOR, JNK/Stat and Erk/NF-κB pathways and IL1β, MIP2, IFN-γ, TNF-α and RANTES) and dysfunction of normal apoptotic pathway. Our study shows how long term AgNPs exposure may promote ultrastructural damage to kidney causing inflammation and expression of cell survival factors. These changes, in the long term, could lead to inhibition of the beneficial apoptotic pathway and promotion of necrotic cell death in kidneys.

Health Impact of Silver Nanoparticles: A Review of the Biodistribution and Toxicity Following Various Routes of Exposure

“…Changes in blood parameters indicated by a significant elevation of ALT, AST, and hepatoxicity, shown by histological damages (necrosis, hepatocytic inflammation, and the resultant aggregation of lymphocytes in liver tissue) were also observed in a study that evaluated the toxic effect of 14 days of oral exposure to AgNPs (40 nm) at doses 20 and 50 ppm in BALB/C mice [176]. Moreover, Tiwari et al [177] determined the effect of 60 days AgNPs (10-40 nm) treatment on the kidneys of female Wistar rats at doses of 50 and 200 ppm, and they demonstrated significant mitochondrial damage, increased levels of serum creatinine, and early toxicity markers such as KIM-1, clusterin and osteopontin. Abbreviations: lung (Lu), liver (Li), spleen (Sp), kidney (Ki), brain (Br), heart (Ht), bladder (Bl), uterus (Ut), thymus (Th), cecum (Ce), placenta (Pl), polyvinylpyrrolidone (PVP), and citrate (CT).…”

Long‐Term Prevention of Bacterial Infection and Enhanced Osteoinductivity of a Hybrid Coating with Selective Silver Toxicity

“…For example, AgNPs treatment of osteoblasts decreases their viability and inhibits their differentiation. [6c] As previously reported, oral AgNPs treatment at the dose of 200 ppm could also cause weight decrease and loss of kidney function in a rat model . In another study, Kim et al reported that high‐dose (500 mg kg −1 d −1 ) AgNPs intake could cause significant liver damage in both male and female rats, with 125 mg kg −1 d −1 being considered as the lowest observable adverse‐effect level of AgNPs oral toxicity.…”

Nickel Nanoparticles Induced Nephrotoxicity in Rats: Influence of Particle Size

“…The increased level of creatinine in the serum of the experimental animals treated with NiNPs may refer to the affected kidney functions, such as the glomerular filtration rate, which may be due to the accumulation of NiNPs in the kidney. Such increase in serum creatinine level was observed after exposure to other nanoparticles such as sliver NPs (Tiwari et al, 2017).…”