Mechanisms of TiO₂ nanoparticle‐induced neuronal apoptosis in rat primary cultured hippocampal neurons

Abstract

Exposure to titanium dioxide nanoparticles (TiO2 NPs) has been demonstrated to decrease learning and memory of animals. However, whether the impacts of these NPs on the recognition function are involved in hippocamal neuron damages is poorly understood. In this study, primary cultured hippocampal neurons from one-day-old fetal Sprague-Dawley rats were exposed to 5, 15, or 30 µg/mL TiO2 NPs for 24 h, we investigated cell viability, ultrastructure, and mitochondrial membrane potential (MMP), calcium homeostasis, oxidative stress, antioxidant capacity, apoptotic signaling pathway associated with the primary cultured hippocamal neuron apoptosis. Our findings showed that TiO2 NP treatment resulted in reduction of cell viability, promoted lactate dehydrogenase release, apoptosis, and increased neuron apoptotic rate in a dose-dependent manner. Furthermore, TiO2 NPs led to [Ca(2+)]i elevation, and MMP reduction, up-regulated protein expression of cytochrome c, Bax, caspase-3, glucose-regulated protein 78, C/EBP homologous protein and caspase-12, and down-regulated bcl-2 expression in the primary cultured hippocampal neurons. These findings suggested that hippocampal neuron apoptosis caused by TiO2 NPs may be associated with mitochondria-mediated signal pathway and endoplasmic reticulum-mediated signal pathway.

WITHDRAWN: Sevoflurane post-conditioning protects primary rat cortical neurons against oxygen–glucose deprivation/resuscitation via down-regulation in mitochondrial apoptosis axis of Bid, Bim, Puma–Bax and Bak mediated by Erk1/2

“…After washing with PBS twice, images were captured under microscope (Leica, Germany), and then analyzed by image analysis software (Bio-Rad, Hercules, CA, USA). Mitochondrial depolarization of MMP was expressed by the increase of red/green fluorescence intensity ratio [23].…”

Toxicology of nanosized titanium dioxide: an update

“…This result suggested that the exposure of brain cells to TiO 2 NPs could cause brain injury and contribute to the development of neurodegenerative diseases. Sheng et al (2014) also reported that nano-TiO 2 could induce oxidative stress, destabilization of MMP and the intracellular Ca 2+ elevation, and increase the expression of apoptotic proteins in rat primary cultured hippocampal neurons. The neuron apoptosis being involved in mitochondriamediated signal pathway and ER-mediated signal pathway led to the impairment of neuron development, decreasing the ability of learn and memory.…”

Xenobiotic pulmonary exposure and systemic cardiovascular response via neurological links

“…With respect to particulate targets of nerve anatomy and physiology, there are numerous sites where particles may influence neuronal activity and have dire consequences on neuronal signaling circuitry, neurotransmitter synthesis, release, and neuronal viability, which may be impacted severely and irreversibly. Within neurons, xenobiotic particles have been shown to interact with cytoskeletal elements and intracellular organelles, ultimately affecting their function, possibly resulting in apoptosis (3,49,107,124). Evidence exists of DNA damage, including single-and double-strand breaks and DNA-protein crosslinks (72); altered overall DNA content (11); as well as mitochondrial DNA methylation (18), following exposure to xenobiotic particles.…”

“…Evidence exists of DNA damage, including single-and double-strand breaks and DNA-protein crosslinks (72); altered overall DNA content (11); as well as mitochondrial DNA methylation (18), following exposure to xenobiotic particles. Furthermore, xenobiotic particles may penetrate to the endoplasmic reticulum and trigger the unfolded protein response, a signaling cascade initiated by the intracellular accumulation of misfolded proteins, as well as oxidative stress (129), a response that may also involve the mitochondria (49,78,107,114) (Fig. 3C).…”