Nanoparticulate TiO2 -mediated inhibition of the Wnt signaling pathway causes dendritic development disorder in cultured rat hippocampal neurons.

Titanium dioxide nanoparticles (TiO2 NPs) are increasingly used in daily life, in industry, and in environmental clearing, but their potential neurodevelopmental toxicity has been highly debated. In this study, we explored whether TiO2 NPs inhibited development of dendritic morphology and identified possible molecular mechanisms associated with this inhibition in primary cultured rat hippocampal neurons. Results showed that TiO2 NPs decreased neurite length, the number of branches and the spine density, and impaired mitochondrial function in the developing neurons. Furthermore, TiO2 NPs significantly reduced the expression of several proteins involved in canonical Wnt3a/β-catenin signaling including Wnt3a, β-catenin, p-GSK-3β, and CyclinD1 and conversely, elevated GSK-3β expression. In addition to altering expression of proteins involved in canonical Wnt3a/β-catenin signaling, TiO2 NPs decreased expression of proteins invovled in non-canonical Wnt signaling, including, MKLP1, CRMP3, ErbB4, and KIF17. Taken together, these results indicate that suppression of dendritic development caused by TiO2 NPs is associated with inhibition of activation of the Wnt/β-catenin pathway or non-canonical Wnt pathway-induced expression of microtubule cytoskeletal components in the developing neurons.