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We encounter endocrine-disrupting chemicals (EDCs), such as Bisphenol-A, oestrogen mimics and flame retardants, in our daily lives. Exposure to these chemicals has been associated with health impacts such as infertility, obesity and cancer.
Traditionally, researchers have investigated the potential effects of endocrine disruptors with 2D cell cultures and animal models. But the former lacks precision, while the latter will ultimately be phased out across the EU as part of the Commission’s commitment to animal welfare.
The SCREENED project offers a single solution for both problems. Coordinated by Lorenzo Moroni, director of the MERLN Institute for Technology-Inspired Regenerative Medicine in the Netherlands, the project team developed innovative 3D cell assays that model a human thyroid.
Organ on a chip
The project aimed to overcome the limitations of traditional 2D cell cultures and animal models, particularly with regards to sensitivity and specificity. As Moroni explains, “most of the tests to screen for EDC effects on the thyroid are still based on 2D cell culture models.” These often use cell lines from diseased origins, as they provide a model that closely resembles the pathological state of the thyroid. However, according to Moroni, “they also offer limited specificity and sensitivity when used for EDC testing.”
The SCREENED team has addressed these limitations by developing three different 3D thyroid models. The first model, developed by the team of Sabine Costagliola at the Université Libre de Bruxelles in Belgium, involves miniature, simplified thyroids known as organoids, derived from human stem cells. These replicate the thyroid hormone production functionality of natural thyroids. “We were able to create, for the first time, a human stem cell-derived thyroid follicle model,” Moroni notes. These organoids are housed in a microfluidic cell culture device, creating an “organ-on-a-chip” model that mimics the natural environment of thyroid cells.
The second model, developed by the University of Parma in Italy, uses specially prepared tissue frameworks that closely match the natural make-up of the thyroid gland, providing improved structure and function. Finally, the third model involves 3D-printed structures that replicate the shape and layout of the thyroid gland, including a network of blood vessels to support it. These models are housed in a modular microbioreactor equipped with innovative sensing technology to precisely control cell culture conditions.
Understanding EDCs
The innovative approaches of SCREENED are not limited to these complex 3D structures either. The project has also resulted in a new and better understanding of the EDC’s biological markers, thereby unveiling how these chemicals affect thyroid function. “Our innovation stands on multiple pillars,” Moroni adds. “These cellular new models were cultured in a 3D chip or in a bio-printed construct, both giving higher sensitivity to screened EDCs.”
The potential impacts of SCREENED’s research are profound. By providing high-quality test beds, the project could enable the detection of chemicals with endocrine-disrupting effects at much earlier stages of exposure than before. “The higher specificity and sensitivity to EDCs that we have demonstrated could provide a high-quality test bed to screen for EDCs’ putative effects at lower doses,” says Moroni.
Furthermore, the adoption of these advanced 3D assays could reduce reliance on animal testing, aligning with ethical considerations and regulatory trends towards more humane research methods. This approach helps us understand how exposure to certain substances can lead to negative effects on thyroid development and function. By using advanced techniques to study proteins and genes, along with computer models, scientists can trace the steps from the initial exposure to the final health impact. This method supports the idea of mapping out the entire process to better predict and prevent harmful outcomes.
Looking ahead, Moroni and his team have plans to further their research. Despite not having secured further funding yet, the SCREENED team remains optimistic about future opportunities to continue their groundbreaking work.