The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds

Juliette Legler , Daniel Zalko (1) , Fabien Jourdan (1) , Miriam Jacobs (2) , Bernard Fromenty (3) , Patrick Balaguer (4) , William Bourguet (5) , Vesna Munic Kos (6) , Angel Nadal (7) , Claire Beausoleil (8) , Susana Cristobal (9) , Sylvie Rémy (10) , Sibylle Ermler (11) , Luigi Margiotta-Casaluci (11) , Julian Griffin (12) , Bruce Blumberg (13) , Christophe Chesné (14) , Sebastian Hoffmann (15) , Patrik L Andersson (16) , Jorke H Kamstra (17)

1 ToxAlim-MeX - Métabolisme et Xénobiotiques
2 Centre for Radiation, Chemical and Environmental Hazards
3 NuMeCan - Nutrition, Métabolismes et Cancer
4 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
5 CBS - Centre de Biochimie Structurale [Montpellier]
6 Karolinska Institutet [Stockholm]
7 UMH - Universidad Miguel Hernández [Elche]
8 DER - Direction de l'Evaluation des Risques
9 LIU - Linköping University
10 VITO - Flemish Institute for Technological Research
11 Brunel University London [Uxbridge]
12 Imperial College London
13 UC Irvine - University of California [Irvine]
14 Biopredic International [Saint-Grégoire]
15 Seh consulting
16 Umeå University
17 Universiteit Utrecht / Utrecht University [Utrecht]

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 Int. Int. J. Mol. Sci. 2020, 21, 3480 2 of 18 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.

Mots clés: diabetes; risk assessment; chemicals; endocrine; obesity

Domaines: Sciences du Vivant [q-bio]; Alimentation et Nutrition; Santé publique et épidémiologie; Toxicologie

Juliette Legler, Daniel Zalko, Fabien Jourdan, Miriam Jacobs, Bernard Fromenty, et al.. The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds. inrae. 2020, pp.1-18/3480. ⟨hal-02638423v2⟩