Periodic Reporting for period 2 - EDCMET (Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways)
Periodo di rendicontazione: 2020-07-01 al 2021-12-31
NR-coregulator interaction assays are available for ten NRs. Reporter gene assays for predicting the activation of NRs involved in the regulation of metabolic pathways have been developed and evaluated by following the NCATS and OECD Framework to ensure robustness, reproducibility, and transferability of the assays. Mitochondrial respiration assays have been developed to enable assessment of functional effects of EDs on cellular level in hepatic cell models. High-throughput, fluorescence-based AdipoRed assay is available to evaluate the steatotic effects of EDs. A set of ED chemicals has been screened across the assay panel and further compound testing is ongoing. Steps towards regulatory implementation of the developed assays have been initiated in collaboration with EURION and OECD expert group.
Standard Operating Procedures (SOPs) have been developed for insulin tolerance and glucose tolerance tests as well as for inducing obesity, insulin resistance, and non-alcoholic fatty liver disease using high-fat diet in mice. Studies on ED effects on vulnerable individuals (obesity, in utero) are ongoing. Liver transcriptomics and biochemical analyses following pregnane X receptor activation have revealed widespread effects and mechanistic details on effects of xenobiotics on cholesterol synthesis. The biological knowledge gained from in vitro and in vivo studies, alongside further interrogation of legacy data, will also support AOP development later in the project.
Levels of selected ED compounds have been analysed from cohort samples and analyses on potential associations of exposure levels and systemic metabolism as well as health outcomes are underway. Several scientific papers on the epidemiological findings have been published and a workshop is planned for 2022 to discuss results and further plans.
Information on developed assays, ED test compounds, experimental protocols and cohorts have been shared and discussed in EURION meetings and working groups.
Endocrine-related diseases represent a high cost for healthcare systems in the EU countries and metabolic effects of EDs are poorly understood. EDCMET will increase the knowledge on metabolic diseases by characterization of the affected critical pathways in liver using the AOP approach. EDCMET will also aid in the development of novel biomarkers for metabolic diseases and provide a relevant base for assessing adverse human health effects of environmental chemicals. The availability of fast and cheaper test systems can stimulate research around environmental chemicals and contribute to safer marketed products and thereby have a positive impact on the environment.