Titanium Dioxide Inhibits Hippocampal Neuronal Synapse Growth Through the Brain-Derived Neurotrophic Factor-Tyrosine Kinase Receptor B Signaling Pathway.

Abstract

Nanoparticulate titanium dioxide (nano-TiO₂) is a commonly used nanoparticle material and has been widely used in the fields of medicine, cosmetics, construction, and environmental protection. Numerous studies have demonstrated that nano-TiO₂ has toxic effects on neuronal development, which lead to defects in learning and memory functions. However, it is still unclear whether nano-TiO₂ inhibits the development of synapse and the underlying molecular mechanism is still unknown. In this study, nano-TiO₂ was administered to rat primary hippocampal neurons for 24 h to investigate the underlying molecular mechanisms behind the inhibition of neuronal synaptic development by nano-TiO₂. We used hippocampal neurons as a model to study the effect of nano-TiO₂ on synaptic development. Our results demonstrated that dendritic development that represented synaptic plasticity in hippocampal neurons was significantly inhibited in a concentration-dependent manner after exposure to nano-TiO₂ for 24 h. Experiments with varying concentrations of nano-TiO₂ (5, 15, and 30 g/mL) indicated that the apoptotic rate of hippocampal neurons increased, development of neuronal synapses were inhibited, and synaptic densities decreased by 24.29%, 54.29%, and 72.86%, respectively, in post-treatment with nano-TiO₂. Furthermore, the results indicated that the expressions of Synapsin I (SYN I) and postsynaptic density 95 (PSD95) in neuron synapse were also significantly inhibited, particularly SYN I decreased by 18.43%, 37.2%, and 51.6%, and PSD95 decreased by 16.02%, 24.06%, and 38.74% after treatment with varying concentrations of nano-TiO₂, respectively. In addition, experiments to assess the BDNF-TrkB signaling pathway indicated that nano-TiO₂ inhibited the expressions of key proteins in the downstream MEK/ERK and PI3K/Akt signaling pathways by inhibiting the expression of BDNF. With concentrations of nano-TiO₂ at 5, 15, and 30 μg/mL, the expression of BDNF decreased by 22.64%, 33.3%, and 53.58% compared with the control group. Further, the expression ratios of downstream key proteins p-CREB/CREB decreased by 3.03%, 18.11%, and 30.57%; p-ERK1/2/ERK1/2 ratios decreased by 19.11%, 28.82%, and 58.09%, and p-Akt1/Akt1 ratios decreased by 1.92%, 27.79%, and 41.33%, respectively. These results demonstrated that nano-TiO₂ inhibited the normal function of the BDNF-TrkB signaling pathway, which is closely related to neuronal synapse. Thus, it can be hypothesized that the inhibition of neuronal synaptic growth by nano-TiO₂ may be related to the inhibition of BDNF-TrkB signaling pathway.