Nanosize Titanium Dioxide Stimulates Reactive Oxygen Species in Brain Microglia and Damages Neurons in Vitro

Abstract

BackgroundTitanium dioxide is a widely used nanomaterial whose photo-reactivity suggests that it could damage biological targets (e.g., brain) through oxidative stress (OS).ObjectivesBrain cultures of immortalized mouse microglia (BV2), rat dopaminergic (DA) neurons (N27), and primary cultures of embryonic rat striatum, were exposed to Degussa P25, a commercially available TiO2 nanomaterial. Physical properties of P25 were measured under conditions that paralleled biological measures.FindingsP25 rapidly aggregated in physiological buffer (800–1,900 nm; 25°C) and exposure media (~ 330 nm; 37°C), and maintained a negative zeta potential in both buffer (–12.2 ± 1.6 mV) and media (–9.1 ± 1.2 mV). BV2 microglia exposed to P25 (2.5–120 ppm) responded with an immediate and prolonged release of reactive oxygen species (ROS). Hoechst nuclear stain was reduced after 24-hr (≥100 ppm) and 48-hr (≥2.5 ppm) exposure. Microarray analysis on P25-exposed BV2 microglia indicated up-regulation of inflammatory, apoptotic, and cell cycling pathways and down-regulation of energy metabolism. P25 (2.5–120 ppm) stimulated increases of intracellular ATP and caspase 3/7 activity in isolated N27 neurons (24–48 hr) but did not produce cytotoxicity after 72-hr exposure. Primary cultures of rat striatum exposed to P25 (5 ppm) showed a reduction of immunohistochemically stained neurons and microscopic evidence of neuronal apoptosis after 6-hr exposure. These findings indicate that P25 stimulates ROS in BV2 microglia and is nontoxic to isolated N27 neurons. However, P25 rapidly damages neurons at low concentrations in complex brain cultures, plausibly though microglial generated ROS.

Differences in Magnetic Particle Uptake by CNS Neuroglial Subclasses: Implications for Neural Tissue Engineering

“…Extensive particle accumulation in conjunction with iron toxicity post-degradation is the likely pathological correlate of MP toxicity in these cells [47]. By contrast, in the other cell types, particles appeared to be relatively stable morphologically with negligible associated toxicity.…”

Nanoparticle accumulation and transcytosis in brain endothelial cell layers

“…TiO 2 is one of most frequently used materials in commercial products, e.g., cosmetics and dental care, 66 and concerns regarding the effects of TiO 2 nanoparticles on human health, including neurological damage, 67,68 have been raised. However, the fate of TiO 2 nanoparticles upon exposure to the human BBB has not been clearly defined to date.…”

Role of Carnosine and Melatonin in Ameliorating Cardiotoxicity of Titanium Dioxide Nanoparticles in the Rats

“…Serum levels of immunoglobulin G, TNF-α, CRP and IL-6 were also elevated. Some studies have shown that TiO 2 nanoparticles could increase the reactive oxygen species, which in turn depleted cellular antioxidants (Long et al 2007;Lu et al 2008;Park et al 2008;Wang et al 2008;Mallik et al 2011). Adverse biological effects exerted by NPs is thought to be caused by the oxidative stress (Donaldson et al 2001;Gurr et al 2005;Nel et al 2006) and results in DNA oxidation in the heart, DNA strand breaks, inflammation and even cell necrosis (Sheng et al 2013).…”

“…It was thought that TiO 2 -NPs were non-toxic mineral (Sager et al 2008). However, many studies suggested that titanium dioxide nanoparticles could be more toxic than their original materials (Long et al 2007;Zhao Jet al 2009;Zhao Jet al 2011;Magaye and Zhao 2012;Liu K et al 2013). The exposure to nanoparticle can be either accidentally due to occupational exposure, or intentionally through different routs such as nose by inhalation, mouth by ingestion, skin contact or intravenous injection (Zhu et al 2012;Khan and Maskat 2014).…”