Titanium dioxide nanoparticles induce neurotoxicity through PI3K/Akt-mediated mitochondrial apoptosis.

Abstract

Concerns about chronic exposure to titanium dioxide nanoparticles (TiO2-NPs) have increased because of their widespread use in consumer products and subsequent environmental release. Previous studies have shown that TiO2-NPs exert neurotoxic effects and may contribute to Parkinson's disease (PD)-related neurodegenerative processes. However, the molecular mechanisms underlying TiO2-NPs-induced neurotoxicity remain unclear. We investigated these effects and their potential mechanisms in A53T α-synuclein transgenic mice and SH-SY5Y cells. Repeated oral exposure to TiO2-NPs for two months dose-dependently aggravated motor dysfunction and neuronal degeneration in the substantia nigra pars compacta at 1, 10, and 50mg/kg body weight. In SH‑SY5Y cells, exposure to TiO2‑NPs for 48h at 0.01, 0.1, 1, 10, 50, and 100mg/L reduced cell viability in a concentration-dependent manner, impaired mitochondrial function, increased reactive oxygen species (ROS) production and promoted apoptosis. Western blotting showed that TiO2-NPs inhibited PI3K/Akt signaling and altered mitochondrial apoptosis-related proteins, including Bcl-2, Bax, cytochrome C (Cyt C) and caspase-3. The PI3K agonist insulin-like growth factor-1 (IGF-1) partly attenuated these changes. These findings provide mechanistic evidence for TiO2-NPs-induced neurotoxicity and may support the health risk assessment and safe application of TiO2-NPs.