Towards a Better System for Identifying Endocrine Disruptors

Institute

Coordinated by Inserm, the European project OBERON aims to develop panels of tests that will – eventually – make it possible to determine with more accuracy and certitude how compounds suspected of being endocrine disruptors might induce metabolic disorders and, ultimately, to identify these compounds.

In order to improve the knowledge and identification of substances suspected of being endocrine disruptors (EDs), the European Union is funding the OBERON program (Integrative strategy of testing systems for the identification of endocrine disruptors related to metabolic disorders). The objective? Build a panel of tests for studying the effects of these substances on the metabolic system and prepare the validation of the most promising tests. These can then be used in a regulatory framework to reveal these harmful effects and analyze the various biological steps leading to them, particularly those that involve the endocrine system. A better understanding of these steps will enable Adverse Outcome Pathways (AOPs) to be established for each substance.

Why the need for OBERON?

Endocrine disruptors are the subject of increasing attention from the public authorities, citizens, media and researchers. While these substances are suspected of interacting with our hormone system, demonstrating this with certainty remains difficult given that the endocrine system is complex and difficult to study in its entirety. In addition, the toxicity of the suspected disruptors is probably related to exposure over the long-term, in which repeated doses no doubt have distinct effects according to whether they are high or low, alone or in combination with other high-risk substances (cocktail effect), and above all depending on the period of development during which the exposure occurs.

In such a context, it appears essential to gain a deeper understanding of these mechanisms, for which validated and complementary tests would be needed in order to have the most in-depth view possible of the impact of each chemical compound. The European Union therefore selected eight projects aiming to improve how these substances are studied and tested in the various physiopathological domains: OBERON is devoted to the incidence of EDs on metabolic disorders. Others focus on thyroid disorders, their neurotoxicity, reproductive disorders... These eight projects make up the EURION cluster, which will be coordinated by Inserm for the first 18 months.

An innovative approach aiming for maximum coverage

No fewer than 11 partners from 6 European countries will participate in the OBERON consortium. Karine Audouze, researcher at Inserm Unit 1124* specialized in bioinformatics, will conduct systems biology studies. She will coordinate the various teams over a 5-year period: "Our network multidisciplinary research will deepen knowledge of EDs in the field of metabolic diseases. Its originality lies in offering an integrated approach: based on experimental tests, epidemiological and clinical data from population cohorts and IT modeling, we will be able to enrich the AOPs and ultimately enable regulators and legislators - the European Union, OECD - to have validated tools".

In practice, the basis of these studies will be formed by ten compounds from the following seven chemical families: bisphenols, phthalates, polyfluoroalkyls, heavy metals, organochlorine insecticides, parabens and dioxins. For each compound, several approaches will be developed:

  • tests on 2D and 3D cells and tissues, with the latter (organoids) used to better reflect the reality of the tissues in vivo;
  • in vivo tests on the zebrafish: its easy-to-study metabolism can be used to model human metabolic diseases;
  • -omics techniques: transcriptomics (study of the variation of gene expression), lipidomics and metabolomics (impact of the EDs on the metabolism);
  • systems biology methods to cross-check the experimental data and existing scientific data, in order to develop the AOPs and improve knowledge of the compounds’ action mechanisms.

"The teams selected cover a broad range of expertise – sometimes complementary, sometimes similar. The aim is to propose various tests for a same problem and then cross-validate, each validating the test of the other, explains the researcher. Once a test has been developed and validated, we will then be able to extend its application to other compounds whose chemical structure and/or mechanism of interaction with our biology are close".

OBERON has been allocated a budget of 5.9 million euro over 5 years. The French partners involved are Inserm (Unit 1124, Paris; Unit 1085 - IRSET, Rennes; Unit 1211, Bordeaux), Inserm Transfert, as well as Ineris and Anses.

Note:
* Unit 1124 Inserm/Université Paris Descartes, Environmental Toxicology, Therapeutic Targets, Cell Signaling and Biomarkers, Paris.