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Title: Investigations on the toxicity of nanoparticles
Keywords: nanotoxicology,silver nanoparticles, platinum nanoparticles, cytotoxicity, genotoxicity, inflammation
Issue Date: 18-Dec-2009
Citation: ASHARANI PEZHUMMOOTTIL VASUDEVAN NAIR (2009-12-18). Investigations on the toxicity of nanoparticles. ScholarBank@NUS Repository.
Abstract: Nanoparticles, even though small in dimension, have a huge impact on the economy. Nanotechnology is a multidisciplinary approach that is perceived to be building up the future of coming era. Thus, it is absolutely necessary to understand the health impact of the nanomaterials to facilitate a safe and sustainable progression of the nanotechnology. Nanotoxicology is one of the latest branches of nanotechnology that investigate the biological properties of nanoparticles. Previous studies in nanotoxicology demonstrated adverse health effects of many commercialised nanomaterials. Based on the early reports, a robust research was initiated to understand the toxicity of nanomaterials currently in demand. In the studies described in this thesis, we have investigated the toxicity associated with silver and platinum nanoparticles both in vitro and in vivo. The nanoparticles were screened using zebrafish embryos and human cell lines, to identify potential toxicity of the nanoparticles, which were further investigated to elucidate the mechanism of toxicity. In vivo models were monitored for developmental defects such as pericardial and yolk sac edema, bent notochord, malformation of eyes, accumulation of blood etc. The distribution of the toxic nanoparticles inside the embryos were further studied by using transmission electron microscopy of embryo sections, which showed presence of nanoparticles in various developing organs such as brain, heart etc. Nanoparticle deposition was seen in the nucleus of the embryonic cells as well. Cell lines (human lung fibroblasts and human glioblastoma cells) were treated with various nanoparticles to identify the degree of toxicity through viability assay. The mechanism of nanoparticles uptake and bio distribution was studied in detail. Metabolic activity in nanoparticles treated cells were measured using ATP content of cells and mitochondrial activity which indicateded metabolic dysfunction. Generation of reactive oxygen species was measured using fluorescence staining and subsequent flow cytometry analysis which established increased production of hydrogen peroxide and superoxide. Oxidative stress is a common cause of DNA damage in chemical toxicity. Therefore, DNA damage in cells was studied using single cell gel electrophoresis and other genotoxic effects of nanoparticles were looked at by studying chromosomal aberrations (fluorescence insitu hybridizations) and micronucleus formation. The nanoparticle treated cells showed increased DNA damage, micronuclei formation and chromosomal aberrations. The fate of the cells was further studied through cell cycle analysis and cell viability-death assay by flow cytometry, which further showed a G2/M arrest and minimal cell death at higher concentration of nanoparticles. Recovery of treated cells was monitored and the ability to form colonies was investigated. Colony formation assay showed absence of colony formation only in silver nanoparticles treated cells, which was more pronounced in cancer cells. The genes and proteins differentially expressed following nanoparticle treatment were identified through pathway specific array, RT-PCR and western blotting. The interactions of silver nanoparticles with cytosolic proteins were studied through isothermal titration calorimetry which evidenced strong interaction with proteins. Platinum nanoparticles exhibited a lesser degree of toxicity compared to silver nanoparticles. In vivo models expose to silver nanoparticles exhibited up regulation of genes involved in DNA damage and oxidative stress. In summary, this study has identified significant toxicity associated with the commercially available nanomaterials. Thus it is ideal that large scale production and commercialisation of such nanoparticles must be minimised until proper guidelines are developed. Also, nano-wate disposal must be taken care of to avoid environmental pollution.
Appears in Collections:Ph.D Theses (Open)

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