Análise dos efeitos do fungicida mancozebe no metabolismo energético de células hepáticas e seu estudo translacional em modelo animal alternativo de Drosophila melanogaster
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Data
2023-04-18
Autores
Oliveira Junior, Fabiano Claudio de
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Universidade Estadual Paulista (Unesp)
Resumo
A doença hepática gordurosa não alcoólica (DHGNA) é atualmente considerada uma epidemia mundial e afeta cerca de 25% da população. Ela é caracterizada quando mais de 5% do peso do fígado corresponde a lipídeos. O uso extensivo de agrotóxicos na agricultura, principalmente no Brasil, tem se tornado um risco para a saúde humana. Essas substâncias podem persistir no meio ambiente, entrar na cadeia de alimentação e estão relacionadas ao desenvolvimento de diferentes patologias, incluindo a DHGNA. O mancozebe (MCZB) encontra-se entre os agrotóxicos mais utilizados no Brasil. Esse fungicida já demonstrou exercer efeitos hepatotóxicos em diferentes organismos. No entanto, seus mecanismos de toxicidade no fígado ainda não são completamente compreendidos. A Drosophila melanogaster é um modelo animal utilizado em estudos translacionais de diferentes patologias humanas graças às semelhanças genéticas e fisiológicas com nossa espécie. Além disso, ela também é utilizada em estudos toxicológicos. Com base nisso, nosso estudo propôs avaliar os efeitos do MCZB no metabolismo energético em modelo celular hepático humano e sua validação na D. melanogaster, visando estabelecer esse organismo como modelo translacional para estudos relacionados a DHGNA. Os resultados obtidos apontam que o MCZB é capaz de induzir a esteatose nas células hepáticas após 72 horas de exposição. No geral, a mensuração da β-oxidação das células expostas ao agrotóxico mostrou-se semelhante ao controle, sugerindo a participação de outras vias no acúmulo de triglicerídeos (TGs) provocado pelo MCZB. A partir de análises bioinformáticas, uma hipótese envolvendo a ação do PXR, PPARγ e FXR foi construída a fim de explicar nossos resultados in vitro. Nos ensaios translacionais, o agrotóxico mostrou ter potencial em induzir a esteatose nas moscas expostas por 5 dias. Porém, após 7 dias de exposição ao MCZB, houve redução dos níveis de TGs e glicose, o que pode ser consequência do estresse oxidativo ou pelas moscas não estarem se alimentando corretamente em decorrência da intoxicação pelo agrotóxico.
Non-alcoholic fatty liver disease (NAFLD) is currently considered a worldwide epidemic and affects approximately 25% of the population. It is characterized when more than 5% of the liver weight corresponds to lipids. The extensive use of pesticides in agriculture, mainly in Brazil, has become a risk to human health. These substances can persist in the environment, enter the food chain and are related to the development of different pathologies, including NAFLD. Mancozeb (MCZB) is among the most used pesticides in Brazil. This fungicide has already shown to exert hepatotoxic effects in different organisms. However, its toxicity mechanisms in the liver are still not completely understood. The Drosophila melanogaster is an animal model used in translational studies of different human pathologies due to their have genetic and physiological similarities with our species. Furthermore, it is also used in toxicological studies. Based on this, our study proposed to evaluate the effects of MCZB on energy metabolism in a human liver cell model and its validation in D. melanogaster, aiming to establish this organism as a translational model for studies related to NAFLD. The results obtained so far indicate that MCZB is able of inducing steatosis in liver cells after 72 hours of exposure. In general, the measurement of β-oxidation of cells exposed to the pesticide was similar to the control, suggesting the participation of other pathways in the accumulation of triglycerides (TGs) caused by MCZB. Based on bioinformatics analyses, a hypothesis involving the action of PXR, PPARγ and FXR was constructed in order to explain our in vitro results. In translational assays, the pesticide showed the potential to induce steatosis in flies exposed for 5 days. However, after 7 days of exposure to MCZB, there was a reduction in the levels of TGs and glucose, which may be a consequence of oxidative stress or because the flies are not feeding properly due to intoxication by the pesticide.
Non-alcoholic fatty liver disease (NAFLD) is currently considered a worldwide epidemic and affects approximately 25% of the population. It is characterized when more than 5% of the liver weight corresponds to lipids. The extensive use of pesticides in agriculture, mainly in Brazil, has become a risk to human health. These substances can persist in the environment, enter the food chain and are related to the development of different pathologies, including NAFLD. Mancozeb (MCZB) is among the most used pesticides in Brazil. This fungicide has already shown to exert hepatotoxic effects in different organisms. However, its toxicity mechanisms in the liver are still not completely understood. The Drosophila melanogaster is an animal model used in translational studies of different human pathologies due to their have genetic and physiological similarities with our species. Furthermore, it is also used in toxicological studies. Based on this, our study proposed to evaluate the effects of MCZB on energy metabolism in a human liver cell model and its validation in D. melanogaster, aiming to establish this organism as a translational model for studies related to NAFLD. The results obtained so far indicate that MCZB is able of inducing steatosis in liver cells after 72 hours of exposure. In general, the measurement of β-oxidation of cells exposed to the pesticide was similar to the control, suggesting the participation of other pathways in the accumulation of triglycerides (TGs) caused by MCZB. Based on bioinformatics analyses, a hypothesis involving the action of PXR, PPARγ and FXR was constructed in order to explain our in vitro results. In translational assays, the pesticide showed the potential to induce steatosis in flies exposed for 5 days. However, after 7 days of exposure to MCZB, there was a reduction in the levels of TGs and glucose, which may be a consequence of oxidative stress or because the flies are not feeding properly due to intoxication by the pesticide.
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Palavras-chave
DHGNA, Metabolismo, Agrotóxicos, Fígado, Cultura de células, Drosophila melanogaster, NAFLD, Metabolism, Pesticides, Liver, Cell culture