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

By Long, Thomas C.; Tajuba, Julianne et al. | Environmental Health Perspectives, November 2007 | Go to article overview

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


Long, Thomas C., Tajuba, Julianne, Sama, Preethi, Saleh, Navid, Swartz, Carol, Parker, Joel, Hester, Susan, Lowry, Gregory V., Veronesi, Bellina, Environmental Health Perspectives


The increased use of engineered nanoparticles in medical, agricultural, industrial, manufacturing, and military sectors Nanosize titanium dioxide is used in a variety of consumer products (e.g., toothpastes, sunscreens, cosmetics, food products) (Kaida et al. 2004), paints and surface coatings (Fisher and Egerton 2001) and in the environmental decontamination of air, soil, and water (Choi et al. 2006; Esterkin et al. 2005). Such widespread use and its potential entry though dermal, ingestion, and inhalation routes suggest that nanosize [TiO.sub.2] could pose an exposure risk to humans, livestock, and eco-relevant species. Recent studies indicate that [TiO.sub.2] is toxic to eco-relevant species (i.e., Escherichia coli, daphnia) (Adams et al. 2006) and mammals (Warheit et al. 2006, 2007). Numerous in vitro studies have reported OS-mediated toxicity in various cell types (Afaq et al. 1998; Beck-Speier et al. 2001; Gurr et al. 2005; Sayes et al. 2006; Wang et al. 2007b; Zhang and Sun 2004). However, the response of nerve cells to nanosize [TiO.sub.2] has not been investigated in vitro or in vivo, except for a companion study (Long et al. 2006).

Because of their size and unusual properties, nanoparticles can enter the body and cross biological barriers relatively unimpeded. Several studies have reported that inhaled or injected nanosize particles enter systemic circulation and migrate to various organs and tissues (Kreyling et al. 2002; Takenaka et al. 2001) where they could accumulate and damage organ systems that are especially sensitive to oxidative stress (OS). The brain is one such organ, being highly vulnerable to OS because of its energy demands, low levels of endogenous scavengers (e.g., vitamin C, catalase, superoxide dismutase) and high cellular concentration of OS targets (i.e., lipids, nucleic acids, and proteins). Recent experimental studies indicate that nanoparticles can cross the blood-brain barrier (Lockman et al. 2004) and enter (in low numbers) the central nervous system (CNS) of exposed animals (Kreyling et al. 2002; Oberdorster et al. 2004).

In the brain, OS damage is mediated by the microglia, a macrophage-like, phagocytic cell that is normally inactive unless confronted by potentially damaging xenobiotics. Their immediate and characteristic response (i.e., "oxidative burst") to foreign stimuli involves cytoplasmic engulfment (i.e., phagocytosis), an increase in metabolic activity, and a change in cell shape, size and proliferation (Block et al. 2007). The NADPH-oxidase driven "oxidative burst" can be monitored by the immediate production and release of superoxide anions ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]) that convert to multiple ROS such as hydrogen peroxide ([H.sub.2][O.sub.2]), hydroxyl radicals, and peroxynitrites. The excess [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] arising from the oxidative burst can diffuse from the microglial plasma membrane and damage the proteins, lipids, and DNA of neighboring cells, especially neurons. Current thinking indicates that microglial-generated ROS underlie neurodegeneration (Block et al. 2007). Although the oxidative burst is the major source of ROS in the activated microglia, [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] is also generated as a by-product of normal mitochondrial energy production (i.e., bioenergetics). This results from the inefficient transfer of electrons along the electron transport chain (ETC) (Fariss et al. 2005). The levels of [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] generated from the ETC are relatively low and efficiently neutralized by matrix-located antioxidant enzyme systems (i.e., endogenous scavengers). However, the levels of ETC-generated [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] can increase significantly if one or more of the enzymatic complexes in the ETC is inhibited.

To examine the possible neurotoxicity of [TiO.sub.2], nerve cells critical to the pathophysiology of neurodegeneration (i. …

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