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Beating Goliath: Generation Of NoveL, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Compounds

Periodic Reporting for period 3 - GOLIATH (Beating Goliath: Generation Of NoveL, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Compounds)

Periodo di rendicontazione: 2022-01-01 al 2023-06-30

The incidence metabolic disorders such as obesity, diabetes and metabolic associated fatty liver disease has reached ‘Goliathan’ proportions. The worldwide increase in metabolic disorders cannot be explained by lifestyle and genetic factors alone; the role of environmental factors in these disorders has been increasingly acknowledged. Exposure to endocrine disrupting chemicals (EDCs) that disrupt metabolism – chemicals collectively referred to as ‘metabolism disrupting chemicals’ (MDCs) – is an environmental risk factor that urgently requires more attention. MDCs are natural and anthropogenic chemicals that have the ability to promote metabolic changes that can ultimately contribute to the development of obesity, diabetes and/or fatty liver in humans. Considering the important role these metabolic alterations can play in the global epidemics of metabolic disorders, it is essential that international chemicals regulations require the identification of MDCs and the assessment of the risk associated with exposure.
Within European chemicals regulations, criteria to identify EDCs have been proposed that require information on a chemical’s endocrine mode of action (MoA) and related adverse effects relevant for human health. However, currently no regulatory in vivo or in vitro tests exist to identify the potential metabolism disrupting effects of chemicals. The need for these tests has been internationally recognized, as without them, comprehensive hazard and risk assessment of chemicals for potential metabolism disrupting activity is virtually impossible.
The overall aim of the GOLIATH project ( is to improve hazard and risk assessment of EDCs by generating novel, optimised, integrated and internationally harmonised approaches for testing metabolic disruption. The GOLIATH project spans the entire spectrum of testing (Figure), from in silico predictive modelling and high-throughput screening, to the development of robust ready-to-use in vitro assays and optimisation of current in vivo testing guidelines. By incorporating novel omics technologies to translate in vitro and in vivo assay outcomes into human health effects, GOLIATH will generate new testing strategies for MDCs, and provide novel insights in the mechanisms by which MDCs disrupt metabolic pathways and induce adverse effects on human health. With a consortium comprised of world-leading experts in endocrinology, physiology, molecular biology, endocrine disruption, toxicology, epidemiology, bioinformatics, test method development, validation and chemical regulation, GOLIATH will be pivotal in the development of an internationally harmonised strategy for testing MDCs.
The overall objectives of the project are:
1. To improve the understanding of the endocrine modes of action of MDCs.
2. To develop assay candidates for metabolic disrupting chemicals based on confirmed MoA and key biological effects in target tissues.
3. To select and develop assay candidates into (pre-)validated test methods, in collaboration with OECD, ensuring test method definition, transferability, inter-laboratory testing and assessment of predictivity, which are prerequisites for their regulatory use.
4. To develop an internationally harmonised, integrated approach to testing and assessment (IATA) of MDCs, using an Adverse Outcome Pathway (AOP) conceptual framework.
1. Review paper on MDCs: A review on current state of science and overview of human exposure to MDCs was published (doi: 10.3390/ijms21103480) to be further elaborated as a detailed review paper with OECD.
2. Chemical selection: Model test chemicals for assays were chosen, as well as chemicals for pre-validation studies in GOLIATH (doi:10.14573/altex.2013.3.331).
3. Advanced in silico screening: EDMON platform is enhanced ( in silico models developed for MDC interaction prediction (doi:10.1021/acs.chemrestox.2c00267).
4. PPAR gamma activity characterization: Importance of species-specific models for endocrine disruption study shown (doi: 10.1021/acs.est.1c04318).
5. Aryl Hydrocarbon characterization: AhR ligand binding domain elucidated (doi: 10.1038/s41467-022-34773-w).
6. Advanced in vitro assay development: Progress on SOPs, test definitions of hepatocyte assays (steatosis, insulin resistance, CYP induction), pancreatic assays (10.3390/ijms24010231 10.3390/ijms23095040) adipocyte differentiation.
7. (Pre)validation of in vitro assays: PPAR gamma and alpha, CYP induction, white adipogenesis assays (pre)validated, manuscripts in preparation.
8. Metabolic profiling: Developing DEXOM algorithm for cell-specific metabolic network characterization (10.1021/acs.est.1c04318) FORUM for chemical-health data mining (10.1093/bioinformatics/btab627).
9. Proteomics progress: Implementing proteome-based thermal shift assay for MDCs in zebrafish (doi: 10.1016/j.jprot.2021.104382) hepatocytes, adipocytes.
10. In vivo relevance: Optimizing transgenic zebrafish model for metabolism disruption post early life MDC exposure.
11. Human relevance: Epidemiological analysis of anthropogenic measures and markers in cohorts relative to prenatal MDC exposure found five overlapping genes (10.3390/ijms24087607).
12. Multi-omics progress: Standardized protocols used for gene expression, metabolomics and lipidomics in various samples.
13. IATA development: Mechanistic networks developed for GOLIATH endpoints, enhancing IATAs for MDCs.
14. Weight of evidence assessment for MDCs: Expert elicitation finalized for defining chemicals as endocrine disruptors.
15. Augmentation of test guidelines: Progress made to include metabolic disruption measures in animal study guidelines.
16. Collaborating with EURION partners ( within working groups.
17. International outreach within EURION through stakeholder meetings, Advisory Board, GOLIATH presentations at events.
In order to progress beyond the state of the art, the expected results of the GOLIATH project are to:
1. Generate a set of robust, well-characterised and ready-to-use in vitro test methods for the effects of MDCs on key target cells in metabolic disorders that will be (pre-)validated and further implemented beyond the duration of the project
2. Realize an integrated approach for testing and assessment of MDCs, that will exceed the duration of GOLIATH, by bringing together new and existing test methods, in a framework that will be internationally harmonised and relevant for regulatory purposes
3. Describe systematically in an AOP framework the mechanisms by which MDCs disrupt metabolism and contribute to metabolic disorders in humans, thereby providing information on the endocrine MoA which is essential for defining endocrine disruption criteria
4. Generate a significant knowledge base on the exposure to and effects of MDCs relevant to the European population, providing a substantial contribution to the weight of evidence for the role of chemicals in metabolic disorders
Figure: Framework of GOLIATH