Research

Genotoxic responses to titanium dioxide nanoparticles and fullerene in gpt delta transgenic MEF cells

An Xu^1,2, Yunfei Chai³, Takehiko Nohmi⁴ and Tom K Hei^1,3*

• * Corresponding author: Tom K Hei tkh1@columbia.edu

Author Affiliations

¹ Center for Radiological Research, College of Physicians & Surgeons, Columbia University, New York, New York, USA

² Key Laboratory of Ion Beam Bioengineering, Institute of Plasma Physics, Chinese Academy of Sciences, Hefei, Anhui, PR China

³ Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York, USA

⁴ Division of Genetics and Mutagenesis, National Institute of Health Science, Tokyo, Japan

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Particle and Fibre Toxicology 2009, 6:3 doi:10.1186/1743-8977-6-3

Published: 20 January 2009

Abstract

Background

Titanium dioxide (TiO₂) nanoparticles and fullerene (C₆₀) are two attractive manufactured nanoparticles with great promise in industrial and medical applications. However, little is known about the genotoxic response of TiO₂ nanoparticles and C₆₀ in mammalian cells. In the present study, we determined the mutation fractions induced by either TiO₂ nanoparticles or C₆₀ in gpt delta transgenic mouse primary embryo fibroblasts (MEF) and identified peroxynitrite anions (ONOO^-) as an essential mediator involved in such process.

Results

Both TiO₂ nanoparticles and C₆₀ dramatically increased the mutation yield, which could be abrogated by concurrent treatment with the endocytosis inhibitor, Nystatin. Under confocal scanning microscopy together with the radical probe dihydrorhodamine 123 (DHR 123), we found that there was a dose-dependent formation of ONOO^- in live MEF cells exposed to either TiO₂ nanoparticles or C₆₀, and the protective effects of antioxidants were demonstrated by the nitric oxide synthase (NOS) inhibitor, N^G-methyl-L-arginine (L-NMMA). Furthermore, suppression of cyclooxygenase-2 (COX-2) activity by using the chemical inhibitor NS-398 significantly reduced mutation frequency of both TiO₂ nanoparticles and C₆₀.

Conclusion

Our results provided novel information that both TiO₂ nanoparticles and C₆₀ were taken up by cells and induced kilo-base pair deletion mutations in a transgenic mouse mutation system. The induction of ONOO^- may be a critical signaling event for nanoparticle genotoxicity.