Periodic Reporting for period 1 - NEMESIS (Novel Effect biomarkers for MEtabolic disruptorS: evidence on health Impacts to answer science and policy needS)
Okres sprawozdawczy: 2024-01-01 do 2025-06-30
Endocrine-disrupting chemicals (EDCs) disturb lipid and glucose metabolism in several metabolically active organs such as liver and pancreas besides being able to interfere with many aspects of hormonal action. There is accumulating evidence linking EDCs or their mixtures with an increased incidence of obesity, atherosclerosis, and type 2 diabetes. Developmental exposure to EDCs can exert life-long, even transgenerational effects and affects the susceptibility to many diseases. However, the metabolic effects of EDCs are still poorly understood and the lack of mechanistic data and predictive models of adverse metabolic outcomes of EDCs hinders their risk assessment.
The “Novel Effect biomarkers for MEtabolic disruptorS: evidence on health Impacts to science and policy needS” (NEMESIS) consortium brings together experts in toxicology, medicine, risk assessment, and social sciences and humanities to respond to the unmet regulatory needs of EDCs within silico, in vitro, in vivo, epidemiological and systems biology data on EDC-mediated metabolic effects in multifactorial models. We will assess mechanistic data on metabolic disruption in liver and pancreas and how EDCs or their mixtures affect the microbiota, enhanced with data on dose-response relationships and the causality of these actions. In addition, NEMESIS will provide human exposure data of EDCs and explore effect biomarkers for metabolic disruption.
NEMESIS’ results will improve assessment of metabolic endpoints in testing guidelines and adopt alternative models to animal testing. Adverse Outcome Pathways (AOP)s and Integrated Approaches to Testing and Assessment (IATA) approaches will be developed to assess adverse metabolic effects of EDCs and improve the risk assessment towards a more holistic approach. Citizens are engaged from the beginning of the project to develop effective risk communication practices on EDCs and to maximize the science-to-policy impact of NEMESIS together with relevant stakeholders.
The “Novel Effect biomarkers for MEtabolic disruptorS: evidence on health Impacts to science and policy needS” (NEMESIS) consortium brings together experts in toxicology, medicine, risk assessment, and social sciences and humanities to respond to the unmet regulatory needs of EDCs within silico, in vitro, in vivo, epidemiological and systems biology data on EDC-mediated metabolic effects in multifactorial models. We will assess mechanistic data on metabolic disruption in liver and pancreas and how EDCs or their mixtures affect the microbiota, enhanced with data on dose-response relationships and the causality of these actions. In addition, NEMESIS will provide human exposure data of EDCs and explore effect biomarkers for metabolic disruption.
NEMESIS’ results will improve assessment of metabolic endpoints in testing guidelines and adopt alternative models to animal testing. Adverse Outcome Pathways (AOP)s and Integrated Approaches to Testing and Assessment (IATA) approaches will be developed to assess adverse metabolic effects of EDCs and improve the risk assessment towards a more holistic approach. Citizens are engaged from the beginning of the project to develop effective risk communication practices on EDCs and to maximize the science-to-policy impact of NEMESIS together with relevant stakeholders.
The NEMESIS project has made substantial progress toward its goal of elucidating how EDCs contribute to metabolic disruption, including insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD) both in adults and in the developing individuals. Central to these efforts has been the successful establishment and deployment of a wide range of experimental models. These include advanced in vitro human systems such as 3D liver microtissues derived from primary hepatocytes as well as hepatic 3D co-cultures and pancreatic islet-like aggregates differentiated from human pluripotent stem cells.
Complementing these, in vivo work in mice and zebrafish have been initiated, enabling comparative analyses across species. Preliminary results suggest that the gut microbiome mediates part of the observed effects of MDCs, with changes in microbial composition and metabolite profiles observed in both model organisms following exposure. Sex-specific responses and developmental effects are being further investigated. The project has also advanced understanding of the interplay between the gut microbiome and MDC toxicity. In both mouse and zebrafish models, MDC exposure has been shown to significantly alter gut microbiota composition and the levels of microbiome-derived metabolites, which may in turn influence host metabolic health. Experiments using gnotobiotic zebrafish have demonstrated altered toxicity responses in the absence of a normal microbiota, highlighting the importance of microbiome-mediated mechanisms.
Mechanistic studies are well underway, employing transcriptomics and metabolomics to characterize the cellular and molecular impacts of MDC exposure. Dose-response analyses have been conducted for endpoints such as hepatic steatosis, mitochondrial function, and nuclear receptor activation. These mechanistic data are being integrated into a multi-omics framework that will enable computational modelling of metabolic disruption. A pilot study investigating 4β-hydroxycholesterol as a potential biomarker of EDC exposure is also ongoing, and additional multi-omics biomarker discovery studies are planned. In parallel, human cohort studies have been mobilized to support the project’s translational aims. EDC exposure data from several cohorts have been harmonized, and biological samples are being processed for exposure and metabolomics analyses. These activities will support the identification of early biological signals of MDC-induced metabolic perturbation, particularly in vulnerable populations.
Progress has been made in assessing the toxicity of individual MDCs as well as developing methodologies for mixture risk assessment. A comprehensive mapping of existing approaches for mixture assessment has been completed, and the initial steps toward evaluating the toxicity of realistic EDC mixtures relevant to EU populations have begun. These assessments are informed by toxicokinetic data and will incorporate AOPs and IATA frameworks, developed in collaboration with ENKORE working groups.
Complementing these, in vivo work in mice and zebrafish have been initiated, enabling comparative analyses across species. Preliminary results suggest that the gut microbiome mediates part of the observed effects of MDCs, with changes in microbial composition and metabolite profiles observed in both model organisms following exposure. Sex-specific responses and developmental effects are being further investigated. The project has also advanced understanding of the interplay between the gut microbiome and MDC toxicity. In both mouse and zebrafish models, MDC exposure has been shown to significantly alter gut microbiota composition and the levels of microbiome-derived metabolites, which may in turn influence host metabolic health. Experiments using gnotobiotic zebrafish have demonstrated altered toxicity responses in the absence of a normal microbiota, highlighting the importance of microbiome-mediated mechanisms.
Mechanistic studies are well underway, employing transcriptomics and metabolomics to characterize the cellular and molecular impacts of MDC exposure. Dose-response analyses have been conducted for endpoints such as hepatic steatosis, mitochondrial function, and nuclear receptor activation. These mechanistic data are being integrated into a multi-omics framework that will enable computational modelling of metabolic disruption. A pilot study investigating 4β-hydroxycholesterol as a potential biomarker of EDC exposure is also ongoing, and additional multi-omics biomarker discovery studies are planned. In parallel, human cohort studies have been mobilized to support the project’s translational aims. EDC exposure data from several cohorts have been harmonized, and biological samples are being processed for exposure and metabolomics analyses. These activities will support the identification of early biological signals of MDC-induced metabolic perturbation, particularly in vulnerable populations.
Progress has been made in assessing the toxicity of individual MDCs as well as developing methodologies for mixture risk assessment. A comprehensive mapping of existing approaches for mixture assessment has been completed, and the initial steps toward evaluating the toxicity of realistic EDC mixtures relevant to EU populations have begun. These assessments are informed by toxicokinetic data and will incorporate AOPs and IATA frameworks, developed in collaboration with ENKORE working groups.
Chemical-induced metabolism disruption is an under-researched area, even though exposure to EDCs and various EDC-mixtures is practically inevitable. Thus, by addressing these knowledge gaps that hinder their evidence-based risk assessment and regulation of EDCs, the NEMESIS project expects to significantly contribute to a safer and healthier EU. NEMESIS will provide mechanistic information on adverse metabolic effects of EDCs and their mixtures, insights into the most sensitive windows of susceptibility, sex and multigenerational effects as well as novel biomarkers, such as 4β-hydroxycholesterol, for metabolic disruption. NEMESIS aims to build a comprehensive understanding of EDC exposure patterns and their potential health impacts by leveraging existing and de novo data. This collaborative effort ensures a robust foundation for evaluating and mitigating the health risks associated with EDC exposure, while also highlighting areas where additional research and monitoring are needed. The NEMESIS in silico tools and in vitro models will ultimately support the assessment of both functional and developmental toxicity without the need for animal use. NEMESIS data and predictive models for ED risk assessment will be available via a user-friendly cloud platform.