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Previous issue date: 2017-08-28Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESInitially 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 ?g/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.Inicialmente utilizadas em exames de resson?ncia magn?tica no final dos anos 1970 as nanopart?culas de ?xido de ferro (IONPs) possuem hoje vasta aplica??o na ?rea m?dica, em exames de diagn?stico, sistema de envio de drogas, terapias celulares e como agente teragn?stico. Sua alta biocompatibilidade, pequeno tamanho, facilidade de manipula??o e capacidade de responder a aplica??o externa de campo magn?tico lhe oferece grande vantagem sobre outros nanomaterias. Estudos vem demostrando a baixa toxicidade e alta aplicabilidade deste nanomaterial na cl?nica, entretanto algumas quest?es ainda se encontram sem resposta.
Quando em contato com o metabolismo in vivo, nanomateriais podem se comportar de forma a degradar sua estrtutura externa e liberar os ?oins contidos no seu n?cleo. De fato, efeitos adversos relacionado a exposi??o a IONPs est?o majoritariamente relacionadas a libera??o do seu n?cleo elementar; que, quando endocitado, pode ser degradado nos lisossomos e liberar ?ons [Fe]. Altera??es na homeostase de ferro podem ser muito prejudiciais ? c?lula, causando inflama??o, peroxida??o lip?dica e estresse oxidativo. ?rg?os mais sens?veis ao ac?mulo do ferro, como o cora??o, podem apresentar apoptose e degenera??o tecidual. Tais efeitos t?xicos s?o facilmente detectados em estudos utilizando zebrafish como animal modelo. Protocolos com embri?es de zebrafish para an?lise toxicol?gica possuem a vantagem de permitir estudos em grande escala de efeitos no desenvolvimento, sobreviv?ncia, comportamento, express?o g?nica e cardiotoxicidade.
Sob esse cen?rio, esta tese tem como objetivo avaliar a toxicidade de Nanopart?culas de Oxido de Ferro (IONPs) de s?ntese pr?pria e comerciais no modelo experimental zebrafish. An?lise comportamental de locomo??o e express?o g?nica de larvas de zebrafish expostas a Nanopart?culas de ?xido de Ferro puras (sem envolt?rio) e revestidas com dextran indicou uma toxicidade em baixas concentra??es de exposi??o ? nanopart?culas, contrario ao que ? relatado na literatura. Al?m disso, altera??es na via apopt?tica sugere que esta rota esteja intimamente ligada aos efeitos comportamentais encontrados. An?lises posteriores, direcionadas ? cardiotoxicidade sugerem efeitos t?xicos acima de 100 ?g/mL. An?lises gen?mica de express?o nos grupos expostos ? nanopart?cula de ?xido de ferro e ? solu??o de ferro met?lico (usado como controle de positivo de excesso de ferro) permitiram a identifica??o de um paralelo entre toxicidade destas nanopart?culas e as vias de metaboliza??o do ferro
