Enzyme

GCLC

Reactive oxygen species

Cell culture

Biology

Gene

Molecular biology

Chemistry

Antioxidant

Glutathione

Flow cytometry

Signal transduction

Cell biology

Genetics

Biochemistry

Blot

PI3K/AKT/mTOR pathway

Pharmacology

Oxidative Medicine and Cellular Longevity

Objective . The effect of TiO 2 NP exposure on the nervous system and the underlying mechanism remain unclear. The antioxidant effect of TiO 2 NPs at a low dose was newly found in our study, which was different from the effect at high dose. This study is aimed at exploring the mechanism underlying the antioxidant effects of TiO 2 NPs at low dose and the induction of ROS accumulation by TiO 2 NPs at high dose in neurogenic cell lines. Methods . We measured the changes in key molecules in the ROS regulation pathway by western blotting, flow cytometry, and commercial assay kits, and these key molecules were further evaluated to verify their interactions and roles using SH-SY5Y, U251, and SK-N-SH cell lines treated with TiO 2 NPs. Results . Our results showed that the weak antioxidant effect at low dose was caused by mTOR/GCLc-induced GSH overproduction and GSH-Px activity impairment. ROS accumulation at high dose was caused by a mTOR/GCLc-mediated decrease in GSH production, GSH-Px activity impairment, and dramatic ROS production. Furthermore, we found that the ROS species were mainly O 2 -⋅ , and that SOD played a crucial role in reducing O 2 -⋅ levels before the mTOR protein was activated. Conclusion . We revealed the mechanism underlying the bidirectional regulation of ROS induced by TiO 2 NPs at different doses in neurogenic cell lines. Our study emphasized the potential neurotoxic effects of NPs at low dose, which should arouse concern about their safety.

The mTOR/GCLc/GSH Pathway Mediates the Dose-Dependent Bidirectional Regulation of ROS Induced by TiO<sub>2</sub>NPs in Neurogenic Cells

The mTOR/GCLc/GSH Pathway Mediates the Dose-Dependent Bidirectional Regulation of ROS Induced by TiO2NPs in Neurogenic Cells

The mTOR/GCLc/GSH Pathway Mediates the Dose-Dependent Bidirectional Regulation of ROS Induced by TiO₂NPs in Neurogenic Cells