Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity
Introduction
In recent years, TiO2 nanoparticles have increasingly been used in the fields of paints, waste water treatment, sterilization, cosmetics, food additive, bio-medical ceramic and implanted biomaterials largely due to its appropriate physicochemical properties. However, it is these unique characteristics such as small sizes, large surface per mass and high reactivity that nanoparticulate anatase TiO2 can enter the human body quickly, and then imposes potential risks on human health [1], [2]. Several studies have reported that inhaled or injected nanosize particles enter systemic circulation and migrate to various organs and tissues, and exert adverse effects [2], [3], [4], [5], [6], [7], [8]. The administration of TiO2 nanoparticles at 5 g/kg body weight (BW) to mice increased liver weight, and produced hepatocyte necrosis [8]. We recently showed that nanoparticulate anatase TiO2 could cause liver injury and oxidative stress of mice after daily abdominal cavity injection for 14 consecutive days [9], [10], [11]. Nanoparticles can cross the blood–brain barrier [12] and enter (in low numbers) the central nervous system (CNS) of the exposed animals [5], [7]. For instance, largemouth bass that lived in the water containing 500 ppb fullerene were shown to have induced severe brain damages [3]. After the 60-day dermal exposure to hairless mice, TiO2 nanoparticles could penetrate the skin, and was detectable in the brain, although no induced pathological changes were observed [13]. Moreover, TiO2 nanoparticles were shown to stimulate ROS generation in the brain microglia and cause neuron damages in vitro [14]. However, the oxidative toxicity of TiO2 nanoparticles in the brain has not been well studied in vivo to date.
The brain is highly vulnerable to oxidative stress due to its high metabolic rate, the reduced capacity for cellular regeneration (low levels of endogenous scavengers, e.g., vitamin C, catalase, superoxide dismutase), and numerous cellular oxidative stress targets (i.e., lipids, nucleic acids, and proteins) [15]. For instance, nano-sized Fe2O3 particles significantly elevated glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and constitutive NO synthase (cNOS), but decreased the ratio of reduced glutathione (GSH) versus oxidized glutathione (GSSG), thereby causing neurodendron degeneration, membranous structure disruption and lysosome increase in the mouse olfactory bulb [16]. The mice displayed a slight brain lesion after administration of TiO2 nanoparticles (25, 80 and 155 nm) by oral gavage, for the vacuoles as well as the fatty degeneration were observed in the hippocampus of the brain [8]. Wang et al. found that the intranasally instilled TiO2 nanoparticles could migrate into the CNS, deposited in the hippocampus region, and caused oxidative stress and inflammation responses [17]. To gain new insights into the mechanisms underlying the oxidative brain damages caused by nanoparticulate anatase TiO2, here we investigate the accumulation of nanoparticulate anatase TiO2 and the pathological changes in the brain following injection to mice, assess the antioxidant response, and examine the effects of neurochemicals including acetylcholinesterase (AChE) activity, and levels of glutamic acid (Glu) and nitric oxide (NO) in the mouse brain.
Section snippets
Chemicals and preparation
Nanoparticulate anatase TiO2 was prepared via controlled hydrolysis of titanium tetrabutoxide as described previously [18]. In a typical experiment, 1 mL of Ti(OC4H9)4 dissolved in 20 mL of anhydrous isopropanol was added dropwise to 50 mL of double-distilled water adjusted to pH 1.5 with nitric acid under vigorous stirring at room temperature. Then, the temperature was raised to 60 °C and kept 6 h for better crystallization of TiO2 nanoparticles. The resulting translucent colloidal suspension was
Coefficient of brain to body weight
Table 1 shows the coefficients of the brain to body weight, which were expressed as milligrams (wet weight of tissues)/grams (body weight). No significant differences were found in the body weight of seven groups. With increasing dosages, the coefficients of the brain to body weight were decreased gradually, and those of 50, 100, and 150 mg/kg BW nanoparticulate anatase TiO2-treated groups and 150 mg/kg BW bulk TiO2-treated group were significantly lower than that of the control (p < 0.05 or p <
Discussion
While mice that were treated with nanoparticulate anatase TiO2 and bulk- TiO2 did not significantly alter their body weight (BW), the coefficients of the brain to the body weight were indeed decreased significantly when high-dose nanoparticulate anatase TiO2 and bulk- TiO2 were used (Table 1). As expected, along with increases of nanoparticulate anatase TiO2 dosage used, the accumulation of titanium in the brain was elevated; and we also observed significant pathological changes in the brains
Conclusion
Nanoparticulate anatase TiO2 injected at the mouse abdominal cavity appear able to migrate anteriorly into the brain, then cause the oxidative stress and injury of the brain, and subsequently disturb the normal metabolism of neurochemicals. Oxidative stress we observed showed that the effects of nanoparticulate anatase TiO2 on the mouse brain occurred at the cellular and molecular levels. Our findings imply that the regulation of both ROS and signaling molecules (NO) plays a role in
Acknowledgements
This work was supported by the National Natural Science Foundation of China (grant No. 30901218) and by the Medical Development Foundation of Soochow University of China (grant No. EE120701) and by the National Bringing New Ideas Foundation of Student of China (grant No. 57315427, 57315927).
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Linglan Ma, Jie Liu, Na Li and Jue Wang contributed equally to this work.