PhD Student - Fundaments of nanosilver toxicity - mechanism of nanoparticle dissolution, complexes...
This project aims at elucidating chemistry of the intracellular toxicity of silver nanoparticles (AgNPs), with the focus on zinc-dependent metabolic pathways, in order to assess hazards related to human exposure to AgNPs and to propose preventive actions.
Despite their antimicrobial efficacy, the unregulated AgNPs use in consumer products raised concern as biological studies demonstrated their toxicity. Once internalized, the AgNPs dissolve in cell cytosol, yielding Ag+ ions bound to thiols in a process requiring oxidation of metallic Ag in a reducing environment of the cell. Thiolate Ag(I) complexes result, presumably mostly with glutathione (GSH), the most abundant cellular thiol, but there is evidence that they assault thiol bearing functional proteins, such as nuclear receptors. The exact mechanism and extent of such interactions is unknown. Activity of many thiol proteins depends on Zn(II) ions. Many aspects of intracellular Ag+ toxicity may involve inhibition of these proteins. Our prior research includes Ag+ interactions with model zinc finger peptides (ZF). The substitution of ZF-bound Zn(II) with Ag(I) was rapid, and resulted in a loss of ZF secondary structure. Single Zn(II) ions were replaced with Ag(I) clusters depending on the number of ZF Cys residues (Ag2S2, Ag3S3, or Ag4S4). Loss of ZF structure stipulates loss of its function. We confirmed that for a ZF protein complex with its cognate DNA, which lost its conformation and dissociated from DNA along with the Zn(II) replacement by Ag(I). These experiments strongly suggest that Ag(I) may assault other zinc proteins, such as metallothioneins and enzymes.
The project includes four tasks.
In Task 1 a quantitative study of kinetics and mechanism of dissolution of commonly used AgNPs will be done, with the role of albumin in this process included. The study will use light scattering, electron microscopy, turbidimetry, UV-vis, 109Ag NMR, 1H NMR, ESI-MS and EPR.
In Task 2 Ag(I)-GSH complexes and possible ternary species will be characterized by spectroscopy, ESI-MS and potentiometry, to yield complex affinities as a reference for protein studies.
Task 3 will include a 6-month stay of the doctoral student in the Laboratory of Chemistry and Biology of Metals at the University Grenoble Alpes, France, where the hepatocyte-derived HepG2 cell line has been developed as a biological model for studying the liver toxicity of AgNPs. This stay will help verify the hypotheses formulated in Tasks 1 and 2 regarding the protective role of GSH. For this purpose, cellular GSH will be manipulated, and oxidative stress, mitochondrial function, genomic stability, DNA repair and apoptosis will be studied. The activities of prospective zinc proteins planned for Task 4 will also be followed. Levels of silver, zinc and other metal ions in these cells will be determined at IBB PAS.
In Task 4 the Ag(I) assault on ZF proteins, other DNA-handling zinc proteins, metallothioneins, and zinc enzymes will be studied, and the putative protective GSH effect further investigated on the molecular level of reference. This task will be realized in collaboration with the Laboratory of Food Chemistry and Toxicology, Karlsruhe Institute of Technology (Professor Andrea Hartwig).
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