Applying a quantitative toxicogenomic approach for mechanistic and comparative toxicity assessment of carbon-based nanomaterials

Abstract

The carbon-based nanomaterials (CNMs) are among the most crucial and notable nanomaterials along the inception and progression of nanotechnology, the wide applications of which have expedited nanotechnological research and development. The blooming rate in application and production of CNMs in various fields has prompted accompanying rise in public concerns on their possible toxicological risks and implications to human and ecosystem health. However, our understanding on toxicity and potential impacts of CNMs is still in its infancy. This dissertation proposed to employ a newly established high-throughput quantitative toxicogenomics-based 3-dimensional (3-D) protein expression profiling technique with yeast cells to conduct a systematic and comprehensive study in quantitative and mechanistic nanotoxicity assessment of a variety of well-characterized CNMs having different physiochemical and structural properties, including single-walled carbon nanotubes (SWCNTs), graphene (oxide), fullerenes and carbon blacks. The aims are to elucidate the detailed mechanisms of action (MOAs) at the molecular level and modes of action at the cellular level of CNMs, to correlate CNMs' nanotoxicity with their physicochemical and structural properties, and to bridge the knowledge gap and address key challenges in risk and hazard assessment of CNMs. The findings revealed that physicochemical and structural properties can have a significant impact on nanotoxicity of the examined CNMs. All examined CNMs exhibited concentration-dependent toxicity, with DNA stress as the dominant MOA for most CNMs. Specifically, functionalized SWCNTs exhibited higher genotoxicity than unmodified SWCNTs, and the metallic SWCNT showed higher toxicity than the semiconducting one; while the short SWCNT had a higher toxicity level than the long variant, and distinguishable molecular toxicity fingerprints were revealed for the two variants with different lengths. The elemental composition and size of graphene oxides (GOs) exerted impacts on their toxicity, while the oxidation level exhibited no significant effects. The covering and subsequent internalization of GO sheets might be the main mode of action to yeast cells. The investigation in fullerenes, graphene nanoplatelets and carbon blacks with different structures and sizes indicated both these properties impacted toxicity of CNMs. The intracellular reactive oxygen species (ROS) production and phenotypic genotoxicity endpoints were examined by conventional phenotypic bioassays, and the results were well correlated with quantitative molecular endpoints of oxidative and DNA stress, respectively, for the examined CNMs.