Titanium dioxide nanoparticles induce endothelial cell apoptosis via cell membrane oxidative damage and p38, PI3K/Akt, NF-κB signaling pathways modulation

Background: Titanium dioxide nanoparticles (TiO2 NPs) are widely used nanoparticles. Despite, several studies investigated the toxic effects of TiO2 NPs on HUVECs, the results are contradictory and the possible underlying mechanisms remain unclear. Methods: In the present study, we conducted an in vitro study to re-evaluate the possible toxic effects of TiO2 NPs on HUVECs including cell viability, lipids peroxidation, intracellular signaling pathways and nitric oxide syntheses enzymes. Results: Our results demonstrated that, TiO2 NPs were internalized to HUVECs and induce intracellular reactive oxygen species production and cell membrane oxidative damage at the higher concentration. TiO2 NPs induce IKK alpha/beta and Akt phosphorylation and p38 dephosphorylation. After 24 h treatment, pro-inflammatory cytokines, adhesion molecules and chemokine upregulated significantly. TiO2 NPs have no significant effects on eNOS enzymatic activation and iNOS gene expression. At cellular level, apoptosis is the main process that occur in response to TiO2 NPs treatment. HUVECs pretreatment with N-acetyl-c-cysteine (NAC) ameliorate the toxic effects of TiO2 NPs that indicate the oxidative stress is essential in TiO2 NPs -induced toxicity. Total antioxidant capacity show a trend to increase in response to TiO2 NPs exposure. Conclusions: Taken together, this study confirmed the effects of TiO2 NPs on endothelial cells and proposed multiple underlying mechanisms including cell membrane oxidative damage and intracellular processes.