Effects of environmental contaminants presenting uracil-like structure on nonalcoholic pro-steatotic lipid metabolism in coculture cellular model and in the low-cost 3D cultivation model to evaluate its correlations to epigenetic processes

Abstract

Nowadays, the non-alcoholic fatty liver diseases (NAFLD) are considered a worldwide public health problem. These pathologies are characterized by excessive accumulation of fat in the liver caused by different etiologies that can evolve to more severe clinical conditions. Worldwide, the excessive use of chemicals can contribute to the development and evolution of NAFLD, as the pesticide used in Brazil. However, few numbers of studies focused on the mechanisms of action of these environmental contaminants in metabolic processes, which may direct the establishment of the pathology. Recently, our research group established models of liver cell cocultures, responsive to chemical agents and simulators of a prosteatotic environment. Thus, the present proposal aims to use established coculture model to investigate the mechanistic effects of uracil-based structure contaminants (terbacil, bromacil and lenacil) in cellular homeostasis and metabolic effects on lipid metabolism and the establishment of a prosteatotic environment in cultures, correlating to epigenetic mechanisms and pyrimidine biosynthesis. For this, biochemical, cellular, and molecular assays will be performed aiming at the construction of a panel of the effects of the compounds in cellular health. We aim to identify relevant molecules, common to the cellular signaling pathways investigated in cultures incubated with contaminants, which potentially act in the establishment of prosteatotic panel, based on the fact that the disruption of uridine metabolism causes metabolic dysfunctions. Subsequently, aiming at implementing the low-price alternative model of 3D culture as a translational model for the study of etiological agents of NAFLD, the analyses will also be developed in our tridimensional cellular model, to evaluate the parallelism between 2D and 3D cellular models.