Nanoparticulate titanium dioxide-inhibited dendritic development is involved in apoptosis and autophagy of hippocampal neurons in offspring mice

摘要

Background: Numerous studies have demonstrated that, upon maternal exposure, nano-TiO2 can cross the placental barrier, accumulate in offspring animals, and cause neurotoxicity. However, the neurotoxic mechanisms are not fully understood. The aim of this study is to determine the effects of nano-TiO2 on the dendritic outgrowth of hippocampal neurons and confirm the role of apoptosis and excessive autophagy in the neurotoxicity of offspring mice caused by nano-TiO2, as well as its molecular mechanisms. Methods: Pregnant mice were intragastrically administered 1, 2, or 3 mg per kg body weight nano-TiO2 consecutively from prenatal day 7 to postpartum day 21. The ultrastructure, mitochondrial membrane potential (MMP), levels of reactive oxygen species (ROS) and peroxides, and ATP contents, along with the expression of apoptosis- and autophagy-related factors, were investigated. Results: The dendritic length of hippocampal neurons was lower in the group treated with nano-TiO2 than in the control group. Apoptosis, excessive autophagy, and nano-TiO2 aggregation in hippocampal neurons resulted from maternal exposure to nano-TiO2. Maternal exposure to nano-TiO2 also resulted in the over-production of ROS, increases in malondialdehyde and protein carbonylation, reductions in MMP and ATP contents, up-regulation of apoptosis- or autophagy-related factors including histone H2AX at serine 139 (γH2AX), cytochrome C (Cyt C), caspase 3, phosphoinositide 3-kinase (PI3K3C), Beclin 1, c-Jun, LC3I, LC3II, JNK and p-JNK expression, and an increase of LC3II/LC3I, as well as down-regulation of Bcl-2 expression in hippocampal neurons of offspring mice. Conclusions: Maternal exposure to nano-TiO2 inhibited the dendritic outgrowth of hippocampal neurons. This effect is closely associated with excessive autophagy, which is related to severe oxidative stress and alterations in the expressions of apoptosis- and autophagy-related factors in the hippocampal neurons of offspring mice, due to maternal exposure to nano-TiO2.