Abstract
The purpose of this project report is to introduce the European “GOLIATH” project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as “metabolism disrupting compounds” (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world’s first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption—hepatocytes, pancreatic endocrine cells, myocytes and adipocytes—and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.
Highlights
The incidence of obesity and metabolic disorders such as diabetes and non-alcoholic fatty liver disease (NAFLD) has reached “Goliathan” proportions
Given the important role these metabolic alterations can play in the global epidemics of metabolic disorders, international chemical regulations must pay due attention to the identification of metabolism disrupting chemicals” (MDCs) and the assessment of the risk associated with exposure
The GOLIATH project will use reporter cell lines stably expressing the ligand-binding domain (LBD) of human PPARα, peroxisome proliferator-activated receptor γ (PPARγ), LXRα, LXRβ, PXR, or CAR fused to the yeast GAL4 DNA binding domain (DBD) and the luciferase under the control of five GAL4 responsive elements to screen the initial set of GOLIATH compounds (Table 1) as well as a large number of environmental compounds
Summary
The incidence of obesity and metabolic disorders such as diabetes and non-alcoholic fatty liver disease (NAFLD) has reached “Goliathan” proportions. Within European chemicals regulations, criteria to identify EDCs have been recently proposed that require information on a chemical’s endocrine mode of action (MoA) and related adverse effects relevant for human health [5]. The overall aim of the GOLIATH project is to improve hazard assessment of MDCs by generating novel, optimized, integrated, and internationally harmonized approaches for testing metabolic disruption. This initial set of model test chemicals was selected because they have a wide range of mechanisms of action (MoA), and there is existing data from animal and/or human studies that indicate metabolism disrupting effects following exposure.
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