Periodic Reporting for period 1 - EDC-MASLD (Investigation of endocrine-disrupting chemicals as contributors to progression of metabolic dysfunction-associated steatotic liver disease)
Période du rapport: 2024-01-01 au 2025-06-30
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition in Europe, with rising progression to severe forms such as MASH, cirrhosis and liver cancer. Its growing burden creates urgent medical, social and economic challenges, yet no approved therapies exist. Among key drivers, exposure to endocrine-disrupting chemicals (EDCs) remains poorly understood, despite their ubiquity and potential interactions with diet, sex, infections, stress and socioeconomic factors. Addressing this knowledge gap is essential for effective prevention strategies and for informing EU chemical safety policy.
Our project responds to this need through four objectives: (1) characterising how environmental exposures shape the internal exposome and MASLD progression in European cohorts using multi-omics approaches; (2) investigating the mechanisms of EDC-induced liver injury in animal and cell models, with focus on sex and microbiome interactions; (3) building integrative systems biology and screening platforms to assess EDCs and their mixtures in MASLD; and (4) engaging patients, clinicians, policymakers and citizens to translate findings into public health impact, while addressing socioeconomic determinants and healthcare costs.
By combining human data, mechanistic insights, computational tools and social sciences, the project delivers a comprehensive evidence base to improve MASLD prevention, reduce inequalities, and support EU health and environmental policies.
Our project responds to this need through four objectives: (1) characterising how environmental exposures shape the internal exposome and MASLD progression in European cohorts using multi-omics approaches; (2) investigating the mechanisms of EDC-induced liver injury in animal and cell models, with focus on sex and microbiome interactions; (3) building integrative systems biology and screening platforms to assess EDCs and their mixtures in MASLD; and (4) engaging patients, clinicians, policymakers and citizens to translate findings into public health impact, while addressing socioeconomic determinants and healthcare costs.
By combining human data, mechanistic insights, computational tools and social sciences, the project delivers a comprehensive evidence base to improve MASLD prevention, reduce inequalities, and support EU health and environmental policies.
Objective 1 – Characterising exposome–disease links in human cohorts
During RP1, exposome and multi-omics data were collected from the European SLD registry. An inventory of available samples was completed, exposomic analyses performed (n=1600), and steroidomic profiling conducted on a subset (n=463). These datasets form the basis for downstream analyses on MASLD progression. A review on sexual dimorphism in therapy response was submitted, and results from steroidomic profiling were prepared for publication. Milestones M1, M3, M4, M5, M6 and Deliverable 4.1 were achieved.
Objective 2 – Mechanisms of EDC-induced hepatic injury
In vivo and in vitro model systems (murine, zebrafish, 2D/3D hepatocyte models) were established and tested with selected chemicals. A Tier 1 list of chemicals for testing was compiled based on human cohort data and literature review. A pilot study with PFOA demonstrated sex-specific effects and the role of gut microbiota in metabolic outcomes. 3D liver spheroid models were successfully developed and standardised. An article on PFAS exposure in hepatocyte models was published in Environment International.
Objective 3 – Integrative systems biology and screening platforms
A multi-omics platform for chemical exposure analysis was developed and applied to human cohort samples. A new clinical data platform was launched, enabling linkage between exposome, omics, and patient data. Work on Adverse Outcome Pathways (AOPs) was initiated in collaboration with ENKORE, leading to a novel AOP network proposal linking hormone receptor activation to MASH, submitted to OECD. Deliverable 3.1 was completed on time.
Objective 4 – Pathways to impact (scientific and technical work)
Socioeconomic determinants of MASLD were addressed through a joint cohort study (~400 patients, Torino), with study design and analysis plan finalised. A scoping review of European literature on MASLD-related healthcare costs and resource use was conducted, with ~50 studies identified for detailed review. These activities prepare the ground for integrated analysis of biological and social drivers of MASLD progression.
During RP1, exposome and multi-omics data were collected from the European SLD registry. An inventory of available samples was completed, exposomic analyses performed (n=1600), and steroidomic profiling conducted on a subset (n=463). These datasets form the basis for downstream analyses on MASLD progression. A review on sexual dimorphism in therapy response was submitted, and results from steroidomic profiling were prepared for publication. Milestones M1, M3, M4, M5, M6 and Deliverable 4.1 were achieved.
Objective 2 – Mechanisms of EDC-induced hepatic injury
In vivo and in vitro model systems (murine, zebrafish, 2D/3D hepatocyte models) were established and tested with selected chemicals. A Tier 1 list of chemicals for testing was compiled based on human cohort data and literature review. A pilot study with PFOA demonstrated sex-specific effects and the role of gut microbiota in metabolic outcomes. 3D liver spheroid models were successfully developed and standardised. An article on PFAS exposure in hepatocyte models was published in Environment International.
Objective 3 – Integrative systems biology and screening platforms
A multi-omics platform for chemical exposure analysis was developed and applied to human cohort samples. A new clinical data platform was launched, enabling linkage between exposome, omics, and patient data. Work on Adverse Outcome Pathways (AOPs) was initiated in collaboration with ENKORE, leading to a novel AOP network proposal linking hormone receptor activation to MASH, submitted to OECD. Deliverable 3.1 was completed on time.
Objective 4 – Pathways to impact (scientific and technical work)
Socioeconomic determinants of MASLD were addressed through a joint cohort study (~400 patients, Torino), with study design and analysis plan finalised. A scoping review of European literature on MASLD-related healthcare costs and resource use was conducted, with ~50 studies identified for detailed review. These activities prepare the ground for integrated analysis of biological and social drivers of MASLD progression.
During this first reporting period, the project has established the foundations for delivering impactful results. Key achievements include the generation of large-scale exposome and multi-omics datasets from European MASLD cohorts, the development of animal, zebrafish, and human-relevant liver models for testing endocrine-disrupting chemicals (EDCs), and the launch of integrative platforms linking exposure, omics, and clinical data. Early findings highlight sex-specific impacts of exposure and the crucial role of the gut microbiome, underlining the project’s potential to identify vulnerable groups and inform targeted prevention strategies.
While major outcome analyses are planned for subsequent reporting periods, the tools, datasets, and mechanistic insights already developed position the project to make significant contributions to EU chemical safety and health policies. To ensure uptake and success, further integration of multi-omics data, refinement of systems biology models, and continued collaboration with policy stakeholders and regulatory bodies (e.g. OECD, EU chemical strategy initiatives) will be essential. These steps will maximise the translational potential of the results, supporting both scientific progress and policy impact.
While major outcome analyses are planned for subsequent reporting periods, the tools, datasets, and mechanistic insights already developed position the project to make significant contributions to EU chemical safety and health policies. To ensure uptake and success, further integration of multi-omics data, refinement of systems biology models, and continued collaboration with policy stakeholders and regulatory bodies (e.g. OECD, EU chemical strategy initiatives) will be essential. These steps will maximise the translational potential of the results, supporting both scientific progress and policy impact.