Mechanism of toxicity of TiO2 nanoparticles exposure on restraining bone growth of young rats: acting on HDAC9 nucleocytoplasmic translocation-mediated p53 deacetylation involving in growth plate chondrocyte differentiation and ferroptosis.

Excessive intake of Titanium dioxide nanoparticles (TiO2 NPs) in children may lead to abnormal development of cartilage growth plates. Elucidating the mechanism underlying the toxicity of TiO2 NPs on chondrocytes contributes to the prevention and clinical treatment of short stature in children. Herein, we found that TiO2 NPs inhibited chondrocyte proliferation and differentiation. Elevated levels of oxidative stress and activation of ferroptosis were observed in TiO2 NP-exposed chondrocytes. HDAC9 was downregulated in TiO2 NP-exposed chondrocytes, of which overexpression reversed TiO2 NP-mediated detrimental effects. Mechanistically, TiO2 NPs inhibited TDP-43 to impair nucleocytoplasmic translocation and mRNA stability of HDAC9. TDP-43 overexpression protected growth plate chondrocytes from TiO2 NPs exposure, which were blocked by HDAC9 knockdown. TiO2 NPs inhibited p53 deacetylation by suppressing nucleocytoplasmic translocation of HDAC9. HDAC9 upregulated BCL6 and strengthened the interaction of BCL6 and Miz-1 to suppress p21 transcription in chondrocytes. The combination of HDAC9 overexpression and Pifithrin-α efficiently abolished TiO2 NP-mediated detrimental effects in vivo. In conclusion, TiO2 NPs suppresses p53 deacetylation via inhibiting HDAC9 nucleocytoplasmic translocation to impair chondrocyte proliferation and differentiation through IGF1/mTOR signaling.