Avaliação da toxicidade causada pela exposição a IONPS utilizando zebrafish como organismo modelo

Abstract

Initially used in magnetic resonance imaging in the late 1970s, iron oxide nanoparticles (IONPs) have wide application in the medical field today, in diagnostics, drug delivery, cellular therapies and theragnostic. The high biocompatibility, small size, functionalization and ability to respond to an applied magnetic field gives this nanoparticle great advantage over other nanomaterials. Studies have demonstrated the low toxicity and high applicability of this nanomaterial in the clinic, however some questions remain unanswered. When in contact with the in vivo metabolism, nanomaterials can behave in a way to degrade their coating and release the ions contained in their nucleus. In fact, side effects related to exposure to IONPs are mainly related to the release of its elemental nucleus; which, when endocyted, can be degraded inside the lysosomes and release [Fe] ions. Changes in iron homeostasis can be very damaging to the cell, causing inflammation, lipid peroxidation, and oxidative stress. Organs more sensitive to iron accumulation, such as the heart, may demonstrate apoptosis and tissue degeneration. Such toxic effects are easily detected in studies using zebrafish as an animal model. Protocols with zebrafish embryos for toxicological analysis have the advantage of allowing large-scale screening on development, survival, behavior, gene expression and cardiotoxicity. Under this scenario, this thesis aims to evaluate the toxicity of commertial and "in house" synthesis of Iron Oxide Nanoparticles in zebrafish. Behavioral analysis of locomotion and gene expression of zebrafish larvae exposed to uncoated and dextran-coated iron oxide nanoparticles indicated a toxicity at low concentrations of nanoparticle exposure, contrary to what is reported in the literature. In addition, changes in the apoptotic pathway suggest that this route is closely linked to the behavioral effects found. Subsequent analyzes, targeting cardiotoxicity, suggested that concentrations above 100 μg/ml are damaging for the heart. Molecular analyzes in the groups exposed to the iron oxide nanoparticle and to iron solution helped to establish a parallel between the toxicity of these nanoparticles and the pathways of iron metabolism.