Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats
- 482 Downloads
Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50–60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood–brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.
KeywordsMetal nanoparticles Size Age Neurotoxicity Blood–brain barrier Brain edema Neuronal injuries Nitric oxide Neuropathology
This investigation is partially supported by the Air Force Office of Scientific Research (London), Air Force Material Command, USAF, under grant number FA8655-05-1-3065. The US Government is authorized to reproduce and distribute reprints for Government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US Government. Financial support of Swedish Medical Research Council (grant no. 2710, HSS); Astra-Zeneca, Mölndal, Sweden (HSS), Alexander von Humboldt Foundation, Germany (HSS); India-EU Research Co-operation (AS/RP), Ministry of Science and Technology, govt. of India, New Delhi, India (AS/RP); and University Grants Commission, New Delhi, India (HSS); Indian Council of Medical Research, New Delhi, India (HSS) is gratefully acknowledged. The authors have no conflict of interest with any agencies mentioned above.
- 1.Pietroiusti A, Campagnolo L, Fadeel B (2012) Interactions of engineered nanoparticles with organs protected by internal biological barriers. Small doi: 10.1002/smll.201201463. [Epub ahead of print]
- 2.van der Zande M, Vandebriel RJ, Van Doren E, Kramer E, Herrera Rivera Z, Serrano-Rojero CS, Gremmer ER, Mast J, Peters RJ, Hollman PC, Hendriksen PJ, Marvin HJ, Peijnenburg AA, Bouwmeester H (2012) Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. ACS Nano 6:7427–7442CrossRefPubMedGoogle Scholar
- 5.Sharma HS, Ali SF, Hussain SM, Schlager JJ, Sharma A (2009) Influence of engineered nanoparticles from metals on the blood–brain barrier permeability, cerebral blood flow, brain edema and neurotoxicity. An experimental study in the rat and mice using biochemical and morphological approaches. J Nanosci Nanotechnol 9:5055–5072CrossRefPubMedGoogle Scholar
- 9.Sharma HS, Miclescu A, Wiklund L (2011) Cardiac arrest-induced regional blood–brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J Neural Transm 118:87–114CrossRefPubMedGoogle Scholar
- 12.Sharma HS, Olsson Y, Persson S, Nyberg F (1995) Trauma-induced opening of the blood–spinal cord barrier is reduced by indomethacin, an inhibitor of prostaglandin biosynthesis. Experimental observations in the rat using [131I]-sodium, Evans blue and lanthanum as tracers. Restor Neurol Neurosci 7:207–215PubMedGoogle Scholar
- 20.Chen Z, Meng H, Xing G, Yuan H, Zhao F, Liu R, Chang X, Gao X, Wang T, Jia G, Ye C, Chai Z, Zhao Y (2008) Age-related differences in pulmonary and cardiovascular responses to SiO2 nanoparticle inhalation: nanotoxicity has susceptible population. Environ Sci Technol 42:8985–9892CrossRefPubMedGoogle Scholar