Bismuth Oxide Nanoparticles-Induced Subclinical Nephrotoxicity in Male Mice: Role of Oxidative Stress and Apoptosis.

Bismuth's unique properties have led to its widespread use in medical, cosmetic, and electronic applications. However, increasing evidence suggests potential toxicity, particularly from nanoparticle forms that may accumulate in organs. This study investigated the nephrotoxic effects of bismuth oxide nanoparticles (Bi₂O₃ NPs) in male NMRI mice, focusing on underlying molecular mechanisms. Adult mice were divided into control and experimental groups receiving 25-800 mg/kg Bi₂O₃ NPs via oral gavage for 30 days. Kidney function was assessed through serum urea and creatinine measurements. Gene expression analysis evaluated apoptosis markers (Bcl2, Bax, Casp3) and oxidative stress pathways (Nrf2, Hmox1) using RT-PCR. Histopathological examination assessed renal tissue alterations. Results revealed no significant changes in serum urea or creatinine levels. Molecular analysis revealed significant gene alterations: Bax (5.969-fold, p = 0.008) and Casp3 (5.568-fold, p = 0.007) upregulation, alongside Bcl2 downregulation (0.239-fold, p = 0.039), indicating apoptosis. Nrf2 (9.569-fold, p = 0.002) and Hmox1 (4.993-fold, p = 0.039) induction confirmed oxidative stress. Data demonstrate Bi₂O₃ NPs trigger apoptosis and oxidative stress. Histological examination revealed glomerular volume increased to 4.79 ± 0.22 mm3 (800 mg/kg/day, 44% higher than control, p < 0.001) without widespread structural damage. These findings indicate that while Bi₂O₃ NPs do not acutely impair kidney function, they induce cellular-level toxicity through apoptosis and oxidative stress pathways. The compensatory upregulation of antioxidant genes (Nrf2, Hmox1) suggests activation of protective mechanisms. Glomerular hypertrophy may represent an adaptive response to nanoparticle exposure. This study demonstrates that Bi₂O₃ NPs can cause subclinical nephrotoxicity through molecular mechanisms before functional impairment becomes apparent, underscoring the need for further investigation into long-term impacts and threshold doses.