The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds
Juliette Legler, Daniel Zalko, Fabien Jourdan, Miriam N. Jacobs, Bernard Fromenty, Patrick Balaguer, William Bourguet, Vesna Munić Kos, Ãngel Nadal, Claire Beausoleil, Susana Cristóbal, Sylvie Rémy, Sibylle Ermler, Luigi Margiotta‐Casaluci, Julian L. Griffin, Bruce Blumberg, Christophe Chesné, Sebastian Hoffmann, Patrik L. Andersson, Jorke H. Kamstra
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.