Amplified and distinctive genotoxicity of titanium dioxide nanoparticles in transformed yeast reporters with human cytochrome P450 (CYP) genes

Abstract

Titanium dioxide nanoparticles (nTiO2) have been considered a possible carcinogen to humans, but most existing studies have overlooked the role of human enzymes in assessing the genotoxicity of nTiO2. Here, a toxicogenomics-based in vitro genotoxicity assay using a GFP-fused yeast reporter library was employed to elucidate the genotoxic potential and mechanisms of nTiO2. Moreover, two new GFP-fused yeast reporter libraries containing either human CYP1A1 or CYP1A2 genes were constructed by transformation to investigate the potential modulation of nTiO2 genotoxicity in the presence of human CYP enzymes. This study found a lack of appreciable nTiO2 genotoxicity as indicated by the yeast reporter library in the absence of CYP expression but a significantly elevated indication of genotoxicity in either CYP1A1- or CYP1A2-expressing yeast. The intracellular reactive oxygen species (ROS) measurement indicated significantly higher ROS in yeast expressing either enzyme. The detected mitochondrial DNA damage suggested mitochondria as one of the target sites for oxidative damage by nTiO2 in the presence of either one of the CYP enzymes. The results thus indicated that the genotoxicity of nTiO2 was enhanced by human CYP1A1 or CYP1A2 enzyme and was associated with elevated oxidative stress, which suggested that the similar mechanisms could occur in human cells.