Doutorado em Ciências Farmacêuticas (FF)
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Navegando Doutorado em Ciências Farmacêuticas (FF) por Por Orientador "Oliveira, Gisele Augusto Rodrigues de"
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Item Os estágios iniciais do desenvolvimento do zebrafish como modelo alternativo para predizer a toxicidade oral aguda in vivo(Universidade Federal de Goiás, 2021-02-11) Prado, Lara Barroso Brito; Valadares, Marize Campos; http://lattes.cnpq.br/6157755243167018; Oliveira, Gisele Augusto Rodrigues de; http://lattes.cnpq.br/6221735418479539; Oliveira, Danielle Palma de; Rocha, Matheus Lavorenti; Ferreira, Monica Valdyrce dos Anjos Lopes; Alves, Vinícius de Medeiros; Valadares, Marize CamposZebrafish (Danio rerio) early-life stages offer a complex and multicellular system integrating various tissues and differentiation processes. In addition, the zebrafish embryos are structurally and functionally similar to vertebrates, including humans. The acute toxicity test with zebrafish embryos and larvae is already worldwide recognized as an alternative model for ecotoxicological assessment, but it is not include in normative of the Council fot the Control of Animal Experimentation (CONCEA), wich recognize the use of alternative methods validated in research activities in Brazil. This organism model can filling the gap between conventional in vitro and in vivo tests for extrapolation of data for humans, the present study aimed to assess the acute toxicity of substances with different Global Harmonization System (GHS) categories using zebrafish early-life stage to determine LC50 values and compared with in vivo (LD50) acute oral toxicity data from literature, in order to generate a model to prediction acute oral toxicity. This prediction model was evaluated by the application of a drug candidate (LQFM 021). Fifteen substances were evaluated by Fish Embryo Acute Toxicity (FET) test (OECD 236). Parameter evaluated was lethal and sublethal effects after 96 h of exposure. A linear regression- model using the log-transformed of the LC50 values and LD50 was generated for the estimated of LD50 from LC50 values. This model resulted in the following equation Log LD50 (mg/kg) = 0.5749 x log LC50 (mg/L) + 1.284. The method domain of application was 53.33% and the R2 was 0,66. Sublethal effects indicate that substances more toxic presented more abnormalities. The DL50 predicted with FET testing LQFM 021, which classified as category 4 in GHS acute oral systemic toxicity assessment, was of 408.52 mg/kg, which also classified as Category 4. In this work, Quantitative Activity-Activity Relationship (QAAR) models were also developed, based on the data obtained in the FET test with zebrafish. This model using seven toxicological descriptors generated statistically predictive models with R2 values ranging from 0.80 to 0.95 and in combination with the Random Forest method it presented the best performance in the prediction of acute oral toxicity in vivo. Therefore, our results suggest that early-life stages of zebrafish could be at least a refinement in the sense of the principles of the 3R’s to predict acute oral toxicity in vivo, being as an intermediary in the preclinical evaluation between in vitro and in vitro.Item Avaliação toxicológica de uma formulação a base de glifosato e seus principais constituintes sobre o estágio embrio-larval de zebrafish: exposição única e repetida(Universidade Federal de Goiás, 2021-06-12) Rodrigues, Laís de Brito; Oliveira, Gisele Augusto Rodrigues de; http://lattes.cnpq.br/6221735418479539; Oliveira, Gisele Augusto Rodrigues de; Fil, Eric de Souza; Valadares, Marize Campos; Rocha, Thiago Lopes; Sabóia-Morais, Simone Maria Teixeira deGlyphosate (GLY) is the active ingredient of several herbicide formulations used to control weeds in agricultural and non-agricultural areas. Due to intensive use of GLY-based formulations and the repeated applications once weed resistance, some of their components, including the active ingredient, may reach the aquatic environment through direct run-off and leaching. The present study assessed the acute toxicity, after continuous and repeated exposures, and genotoxicity of the GLY-based formulation Atanor 48 (ATN) and its major constituents GLY, surfactant polyethoxylated tallow amine (POEA), as well as the main metabolite of GLY aminomethylphosphonic acid (AMPA) on zebrafish early life stages. Also, we evaluate larvae resilience after ATN, GLY and POEA pulsed-exposure. The toxic effects of these chemicals were evaluated in the fish embryo acute toxicity test with zebrafish (Danio rerio), while genotoxic effects were investigated in the comet assay with cells from zebrafish larvae and rainbow trout gonad-2 (RTG-2). GLY and AMPA caused no acute toxic effect after continuous exposure, while ATN and POEA induced significant lethal effects in zebrafish (LC50-96 h 76.50 mg/L and 5.49 mg/L, respectively. In summary, these data indicate that the lethal effects on zebrafish early-life stages can be ranked in the following order from most to least toxic: POEA > ATN > GLY ≈ AMPA. All compounds were genotoxic to zebrafish larvae (LOEC 1.7 mg/L for GLY, ATN, AMPA and 0.4 mg/L for POEA). Unlike in vivo. POEA induced DNA damage in RTG-2 cells (LOEC 1.6 mg/L), suggesting that it is a direct acting genotoxic agent. GLY caused no acute toxic effect after repeated pulse exposure. However, ATN showed significant mortality (LC50-96 h 148.80 mg/L) after 5 h pulse at 100 mg/L and POEA induced significant toxicity on zebrafish early life stages after 1, 2 and 5 h pulse with LC50-96 h of 43.49 mg/L, 47.23 mg/L and 11.61 mg/L, respectively. Zebrafish was not able to reverse the sublethal effects induced by ATN, GLY and POEA during the recovery period. The toxic effects induced by ATN and POEA after pulsed-exposure were less than continuous exposure. Therefore, its important to evaluate different toxicological endpoints with distinct exposure scenarios to predict the hazards of GLY-based formulations, their components and breakdown product to aquatic biota.