Periodic Reporting for period 1 - HYPIEND (Understanding and preventing the impact of endocrine disruptors on the hypothalamus-pituitary axis in sensitive populations)
Reporting period: 2024-01-01 to 2025-06-30
The HYPIEND project addresses the urgent public health challenge posed by exposure to endocrine-disrupting chemicals (EDCs), particularly during vulnerable life stages such as the perinatal period and pre-puberty. Despite growing awareness of the adverse effects of EDCs, there remains a critical gap in understanding how complex, real-life mixtures affect the hypothalamus-pituitary (HP) axis—a key neuroendocrine regulator of growth, metabolism, and development. HYPIEND combines advanced in vitro, in vivo, and in silico models with epigenetic, molecular, and behavioural analyses to elucidate mechanisms of disruption and develop novel non-invasive biomarkers. Central to its impact pathway are two large-scale, multicentric intervention studies in healthcare and educational settings, designed to empower behavioural change and reduce EDC exposure in sensitive populations. The integration of social sciences—particularly through the Health Action Process Approach (HAPA) model—ensures that the project translates mechanistic insights into effective, sustainable, and context-sensitive public health strategies
During the first 18 months, HYPIEND has made substantial progress in advancing scientific knowledge and technical capacity to assess and mitigate the effects of EDC mixtures on the hypothalamic-pituitary (HP) axis. A robust data-driven framework for mixture selection was established, leading to the identification of thirteen individual EDCs and two candidate EDC mixtures based on co-exposure patterns and QSAR modelling. These two predefined mixtures, along with potential combinations derived from the 13 selected EDCs, are now set to be validated in vitro; however, the results of this stage have been delayed from Month 18 to Month 21. To support this phase, human cell-based assays are being used to characterize cytotoxic, estrogenic, and androgenic effects. In vivo zebrafish models have also been implemented to assess phenotypic disruptions, and one new transgenic zebrafish line is being developed. Organotypic models of the hypothalamus and pituitary were successfully developed, enabling early mechanistic insights into HP disruption. In parallel, in silico models predicting placental and blood-brain barrier permeability were implemented, complementing experimental barrier models. Preparatory work has been implemented to allow rodent experimentation, including approval from Ethical Committes, protocol standardization and establishment of transgenic lines. Foundational work on DNA methylation profiling and extracellular vesicle characterization has begun to support the development of translational biomarkers. Preparatory work was also completed for large-scale interventional studies, including finalization of study protocols and recruitment strategies, approval from Ethical Commitees (including the preparation of the corresponding legal documentation), development of the behavioural multi-component intervention and the booklets for the control groups, other preparatory activities (harmonization of lab material, samples codification, Redcap platform...) initial deployment of the perinatal intervention and recruitment of schools for the prepubertal intervention. Altogether, these activities position HYPIEND to achieve its mid- and long-term scientific goals through a fully integrated translational research pipeline.
HYPIEND has delivered advances beyond the state of the art, establishing a strong foundation for scientific, policy and societal impact. A dedicated knowledge base on EDCs has been prepared, integrating information from multiple sources to support evidence-based assessment. Mixtures of EDCs have been identified based on real co-exposure patterns in the European population, ensuring that research reflects realistic exposure scenarios. Novel in silico models have been developed to predict hormone–receptor interactions and blood–brain barrier permeability. Since liver metabolism can have substantial effect on the toxicity of the chemicals (detoxifying them, or changing into more potent compound), EDCs from main families have been tested in metabolically active system. This allowed to define thirteen biologically relevant EDCs based on exposure data, providing the basis for mechanism-driven hazard identification and risk assessment aligned with real-world exposure. Additionally, an experimental platform has been developed, leveraging human HPA organoids as a new tool to investigate endocrine disruption in the hypothalamic–pituitary axis. HYPIEND has also developed a digital tool providing personalized missions designed to diminish the exposition to EDCs (based on behavioural change techniques), and allowing collection of the information for the clinical studies. The ongoing interventional studies represent an unprecedented effort to generate causal evidence linking EDC exposure reduction to health outcomes. Future exploitation will benefit from early engagement with policymakers, alignment with the Chemical Strategy for Sustainability, and integration into international consortia for regulatory science and standardisation.