Periodic Reporting for period 4 - OBERON (An integrative strategy of testing systems for identification of EDs related to metabolic disorders)
Berichtszeitraum: 2023-01-01 bis 2024-06-30
The main objective of the OBERON project is to develop a new battery of tests to detect endocrine disruptors having an impact on metabolic disorders, without the use of animal
experimentation. Based on the concept of integrated approach for testing and assessment (IATA),
OBERON combines 1) experimental methods, (2) high throughput omics technologies, 3)
epidemiology and human biomonitoring and 4) advanced computational models on functional
endpoints related to metabolism.
experimentation. Based on the concept of integrated approach for testing and assessment (IATA),
OBERON combines 1) experimental methods, (2) high throughput omics technologies, 3)
epidemiology and human biomonitoring and 4) advanced computational models on functional
endpoints related to metabolism.
During the whole project, epidemiological activities took place. They studied datasets from large prospective cohorts and human biomonitoring focusing on infants, children, adolescent, pregnant women and adults’ exposure to pollutants in relation to metabolic health outcomes (including persistent and non-persistent EDs, and cardio-metabolic health considering body mass index (BMI), fat mass, obesity, blood pressure, pulse wave velocity, retinal vessel diameter, diabetes and insulin resistance).
A systematic review of the application of omics technologies in epidemiological studies was done and a panel study to identify multi-omics signatures associated with childhood exposure to non-persistent ED was done. WP1 conducted a case study illustrating the importance of integrating various and complementary new approach methodologies (NAM) with human epidemiology for hazard identification and regulatory decision of EDs.
In WP2, zebrafish bioassays on liver steatosis (StAZ) and on adiposity (ZOT) were developed and optimized with automation of image analysis. They were used to screen the OBERON selected pollutants and decipher their mode of action. The new WP2 task added for the last period of the project allowed the development of EMERGE, a method studying the regulation of cyp3a65 in the zebrafish intestine. The OBERON selected EDs were screened with this method to identify disruptors of intestine metabolism.
In WP3, liver, adipose and pancreatic cell lines were exposed to OBERON compounds (screening) and effects were measured at different levels in the metabolism of the cell: cell viability, carbohydrate and lipid metabolism, lipid droplet accumulation, mitochondrial activity, hormone secretion and gene expression profile. For each tissues, the most promising model was chosen to go onwards and develop ED testing. A specific test model called StaHC was developed all the way to a pre-validation step as the most promising test of the WP to identify endocrine disruptors of metabolism.
In WP4, in silico studies went through with the analyses of existing databases, development of QSAR models and toxicokinetic models. New optimized QSAR models were included on the VEGA platform: https://www.vegahub.eu/(öffnet in neuem Fenster). QSAR models were tested on the OBERON compounds. A PBPK model for bisphenols in the zebrafish eleuthero embryo was finalized. The human PBPK model was parameterized for all the compounds and was applied to translate exposure doses into doses in liver, pancreas and adipose tissue. In addition, biokinetic interactions of co-exposure to 4 phthalates was elaborated. A generic OBERON PBPK model was designed to describe the ADME processes occurring in the human body, so that it can be applied to a wide range of chemicals under appropriate parameterisation.
In WP5, the OBERON Integrated Data Management system was developed in order to properly manage the results obtained in OBERON. Metabolomics and transcriptomics were launched after a pilot study was completed for all the different cell lines studied in the project and for zebrafish. The developed methodology for the multi-omics analysis was applied to datasets from omics analyses of in vivo and in vitro samples. A tool based on artificial intelligence and text mining called AOP-helpFinder, was created and updated. ReadEDTest: A tool to assess the readiness of in vitro test methods under development for identifying endocrine disruptors was also developed https://doi.org/10.1016/j.envint.2023.107910(öffnet in neuem Fenster). The development of an Integrative Testing Strategy (ITS) was achieved during RP4 and described in the deliverable D5.6. And finally, WP5 set up the OBERON Database available online upon registration at https://oberon_data.eu(öffnet in neuem Fenster).
WP6 maintained a close scientific project management at an administrative, financial and legal level by providing partners with management and follow-up tools. WP7 actively worked on the project communication and promotion with an extensive social media campaign on LinkedIn, Instagram and YouTube, both at an institutional level and at a general public level. The collection and analysis of the project’s exploitation and dissemination activities was carried out throughout the life of the project. The IMB reviewed all results to identify any IP measures and possible exploitation measures. OBERON was part of the EURION cluster coordination and took roles in the working groups in addition to participating to cluster meetings.
A systematic review of the application of omics technologies in epidemiological studies was done and a panel study to identify multi-omics signatures associated with childhood exposure to non-persistent ED was done. WP1 conducted a case study illustrating the importance of integrating various and complementary new approach methodologies (NAM) with human epidemiology for hazard identification and regulatory decision of EDs.
In WP2, zebrafish bioassays on liver steatosis (StAZ) and on adiposity (ZOT) were developed and optimized with automation of image analysis. They were used to screen the OBERON selected pollutants and decipher their mode of action. The new WP2 task added for the last period of the project allowed the development of EMERGE, a method studying the regulation of cyp3a65 in the zebrafish intestine. The OBERON selected EDs were screened with this method to identify disruptors of intestine metabolism.
In WP3, liver, adipose and pancreatic cell lines were exposed to OBERON compounds (screening) and effects were measured at different levels in the metabolism of the cell: cell viability, carbohydrate and lipid metabolism, lipid droplet accumulation, mitochondrial activity, hormone secretion and gene expression profile. For each tissues, the most promising model was chosen to go onwards and develop ED testing. A specific test model called StaHC was developed all the way to a pre-validation step as the most promising test of the WP to identify endocrine disruptors of metabolism.
In WP4, in silico studies went through with the analyses of existing databases, development of QSAR models and toxicokinetic models. New optimized QSAR models were included on the VEGA platform: https://www.vegahub.eu/(öffnet in neuem Fenster). QSAR models were tested on the OBERON compounds. A PBPK model for bisphenols in the zebrafish eleuthero embryo was finalized. The human PBPK model was parameterized for all the compounds and was applied to translate exposure doses into doses in liver, pancreas and adipose tissue. In addition, biokinetic interactions of co-exposure to 4 phthalates was elaborated. A generic OBERON PBPK model was designed to describe the ADME processes occurring in the human body, so that it can be applied to a wide range of chemicals under appropriate parameterisation.
In WP5, the OBERON Integrated Data Management system was developed in order to properly manage the results obtained in OBERON. Metabolomics and transcriptomics were launched after a pilot study was completed for all the different cell lines studied in the project and for zebrafish. The developed methodology for the multi-omics analysis was applied to datasets from omics analyses of in vivo and in vitro samples. A tool based on artificial intelligence and text mining called AOP-helpFinder, was created and updated. ReadEDTest: A tool to assess the readiness of in vitro test methods under development for identifying endocrine disruptors was also developed https://doi.org/10.1016/j.envint.2023.107910(öffnet in neuem Fenster). The development of an Integrative Testing Strategy (ITS) was achieved during RP4 and described in the deliverable D5.6. And finally, WP5 set up the OBERON Database available online upon registration at https://oberon_data.eu(öffnet in neuem Fenster).
WP6 maintained a close scientific project management at an administrative, financial and legal level by providing partners with management and follow-up tools. WP7 actively worked on the project communication and promotion with an extensive social media campaign on LinkedIn, Instagram and YouTube, both at an institutional level and at a general public level. The collection and analysis of the project’s exploitation and dissemination activities was carried out throughout the life of the project. The IMB reviewed all results to identify any IP measures and possible exploitation measures. OBERON was part of the EURION cluster coordination and took roles in the working groups in addition to participating to cluster meetings.
• WP1: The analyses of huge cohorts’ data and biomonitoring all along human lifespan provide biomarkers of interest for the study of ED’s in humans.
• WP2: 3 developed methods will be candidates for regulatory use in providing relevant information for environmental and human risk assessments. Artificial Intelligence was used to optimize and increase the efficiency of zebrafish testing. The better efficiency of the test allows for consideration of those methods by industries.
• WP3: Tests on pancreas cells expand the areas of research as new cell lines were used to study a poorly known tissue. At least one developed method will be candidate for regulatory use in providing relevant information for human risk assessments.
• WP4: In silico models will feed databases with new important parameters to consider while studying the actions of pollutants on metabolism and they will help guide in vivo and in vitro experiments and save time, contributing to the 3R.
• WP5: New tools developed like AOPhelpFinder and ReadEDtest considerably help researchers working on test development. AOPhelpFinder helps discovering links between an event like the exposure to a stressor and a health adverse outcome as well as it helps uncovering research gaps, areas of research that lack knowledge hence, contributing to the dynamic of scientific research. The ReadEDTest provides researcher with guidance to validate their methods and tests related to endocrine disruption.
• WP2: 3 developed methods will be candidates for regulatory use in providing relevant information for environmental and human risk assessments. Artificial Intelligence was used to optimize and increase the efficiency of zebrafish testing. The better efficiency of the test allows for consideration of those methods by industries.
• WP3: Tests on pancreas cells expand the areas of research as new cell lines were used to study a poorly known tissue. At least one developed method will be candidate for regulatory use in providing relevant information for human risk assessments.
• WP4: In silico models will feed databases with new important parameters to consider while studying the actions of pollutants on metabolism and they will help guide in vivo and in vitro experiments and save time, contributing to the 3R.
• WP5: New tools developed like AOPhelpFinder and ReadEDtest considerably help researchers working on test development. AOPhelpFinder helps discovering links between an event like the exposure to a stressor and a health adverse outcome as well as it helps uncovering research gaps, areas of research that lack knowledge hence, contributing to the dynamic of scientific research. The ReadEDTest provides researcher with guidance to validate their methods and tests related to endocrine disruption.