Desvendando as vias causadoras de diabesidade induzida pelos desreguladores endócrinos

Overweight and obesity are significant health concerns in the EU, primarily due to their impact on conditions such as T2DM and life expectancy, among others. Therefore, it is crucial to address factors affecting diabesity, such as EDC exposure. So far, most efforts to study diabesity have been focused on the effects of single EDC, and some attempts at elucidating the combination effects of these chemicals have failed due to a poor understanding of the theoretical basis for mixture analysis. The public health standpoint requires considering exposure to diverse chemicals through various routes and sources. Thus, comprehensive strategies must encompass varied EDC mixture sources to grasp their impact on diabesity. Based on the solid expertise of our group in mixture toxicology and diabesity models [11-13], we now aim to tackle a more complex task: investigating potential interactions with EDC that are neither structurally nor pharmacologically related (distinct MoA/AOP) in in vitro and in vivo models of diabesity, focusing on innovative cellular models that account with the interaction of human neutrophils and liver (represented by insulin-resistant and steatotic HepG2 model), adipose tissue (insulin-resistant adipocytes), and THP1-derived macrophages. This comprehensive evaluation aims to establish the mechanistic action of the compounds with an acceptable level of flexibility, accuracy, and reproducibility. The GOAL of this project is to unveil the effects of commonly found EDC, namely polychlorinated biphenyls, benzo(a)pyrene, perchlorate, parabens, dioxins, bisphenols, triclosan, arsenic, di(2-ethylhexyl) phthalate, perfluoroalkyl, dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), diethylstilbestrol (DES) and methoxyacetic acid, in the progression and development of diabesity, identifying the mechanism(s) that are beyond those effects. Specifically, this project aims to: 1. Assess whether the joint effects of EDC can be accurately predicted based on the concentration-response data of the individual components, using the well-established models of concentration addition (CA) and independent action (IA) in in vitro cell models of diabesity; 2. Determine the type of interaction (additive, synergistic or antagonistic) and identify significant combination effects, even when the individual EDC are present in the mixture at low, realistic concentrations, potentially producing no measurable effects (“zero effect" levels); 3. Improve the understanding of the interactions between the components of the mixtures, by measuring specific disease endpoints to elucidate the underlying MoA/AOP; 4. Assess the effects of EDC in a cellular model of NAFLD, evaluating the dysregulation of hepatic glucose metabolism, insulin resistance, steatosis and inflammation; 5. Assess the effects of EDC in adipogenesis, insulin resistance and inflammation, using a monoculture of insulin-resistant adipocytes; 6. Assess the effects of EDC in inflammation using a monoculture of THP-1-derived macrophages; 7. Confirm the in vivo relevance of our findings under optimized experimental settings in Zucker Diabetic Fatty (ZDF) rats. By achieving these aims, this project will play a crucial role in accurately assessing the health risks of EDC (individually and in mixture), informing regulatory policies, and shaping targeted prevention and treatment strategies for EDC-related diabesity.