- Creating new laboratory methods that use liver and non-liver cell systems, including models that mimic how different tissues interact, as well as whole animal zebrafish early life stage tests, to better understand how certain chemicals might contribute to obesity.
- Developing tools and guidelines to help risk assessors more accurately assess the risks of metabolism-disrupting chemicals.
- Identification of metabolic disrupting chemicals to flag substances of concern and assess safe alternatives.
Key messages
- Endocrine Disrupting Chemicals (EDCs ↗) can cause long-lasting changes to how our bodies manage energy and fat storage – what scientist call metabolic disruption.
- Chemicals suspected to trigger these changes are known as metabolism-disrupting chemicals. They may contribute to obesity, type II diabetes, and non-alcoholic fatty liver disease.
- Our project develops and improves New Approach Methodologies (NAMs ↗) to identify and assess metabolism-disrupting chemicals. These include: nuclear receptor models; in vitro test using fat (adipocyte) or pancreatic cells; whole organism test systems, i.e. a zebrafish embryo/larval assays.
- We found that some Bisphenol A alternatives – candidates for safer replacement – can still disrupt metabolic pathways.
Overview
Over the past decade, research into endocrine-disrupting chemicals – substances that interfere with the body's hormonal systems – has revealed that some of these chemicals can cause long-lasting disruptions to metabolism. These substances are now referred to as "metabolism-disrupting chemicals." They are strongly suspected to contribute to the development of metabolic disorders such as obesity, type II diabetes, and non-alcoholic fatty liver disease. These health issues arise in combination with genetic factors, diet, and lifestyle choices. Currently, over 50 million people in Europe suffer from metabolic disorders, and the role of environmental factors, including man-made and natural chemicals, is increasingly recognised.
To classify a substance as an endocrine or metabolism disruptor, specific scientific criteria must be met, as outlined by the World Health Organization (WHO ↗). Despite growing evidence that these chemicals may contribute to the rise of metabolic disorders like obesity and diabetes, there are no dedicated laboratory tests yet that identify the harmful effects of metabolism-disrupting chemicals. This lack of tools makes it challenging to assess the risks these substances pose. Developing reliable methods to identify and evaluate these risks is critically important for public health and regulatory decision-making.
This project focuses on creating New Approach Methodologies (NAMs) to address regulatory gaps. These methods will allow scientists to better identify and assess the risks associated with metabolism-disrupting chemicals. The substances under investigation include chemicals identified on priority lists by the Partnership for the Assessment of Risks from Chemicals (PARC) and European agencies such as the European Chemicals Agency (ECHA ↗) and the European Food Safety Authority (EFSA ↗). By expanding the scope of research to include experimental systems not yet explored and focusing on priority chemical families, this work aims to provide regulators with essential tools to tackle the health challenges posed by these harmful substances.
Achievements & Results
- Improved in vitro test methods by: expanding test chemical datasets; comparing to in vivo data; generating more human-relevant test systems, e.g. 3D cell systems; reducing animal-derived components in the test methods like fetal bovine serum.
- Developed a zebrafish larval assay ↗ that combines exposure to Western diets and aquatic exposure to suspect metabolic disruptors like bisphenol A.
- Screened bisphenol A alternatives for their impact on metabolic disruption.
- Obtained metabolism-disrupting chemicals mechanisms accross multiple levels of the adverse outcome pathway - from receptor interaction to whole organism effects.
- Published a state-of-the-art summary ↗ on metabolism-disrupting chemicals for the scientific and regulatory community.
Policy relevance
- WHO/IPSC (2002) outlines clear criteria classifying endocrine disruptors, but no official criteria yet exits for metabolism-disrupting chemicals.
- Metabolism-disrupting chemicals could potentially be regulated under similar frameworks as EDCs.
- To bridge this gap, validated NAMs are urgently needed.
- Our project develops fit-for-purpose methods that will help regulators detect and manage the risks of metabolism-disrupting chemicals.
Related Publications
Growing evidence suggests that exposure to certain metabolism-disrupting chemicals (MDCs), such as the phthalate plasticiser DEHP, might promote obesity in humans, contributing to the spread of this global health problem. Due to the restriction on the use of phthalates, there has been a shift to safer declared substitutes, including the plasticiser diisononyl-cyclohexane-1,2-dicarboxylate (DINCH). Notwithstanding, recent studies suggest that the primary metabolite monoisononyl-cyclohexane-1,2-dicarboxylic acid ester (MINCH), induces differentiation of human adipocytes and affects enzyme levels in key metabolic pathw
Given the current lack of suitable methods to assess metabolism-disrupting effects on adipose tissue, this study applied metabolomics to human SGBS cells exposed to DINCH and MINCH. Concentration analysis revealed that uptake of MINCH was associated with increased lipid accumulation during adipogenesis. Although intracellular uptake of DINCH was also observed, its limited solubility in cell culture medium hampered the assessment of potential effects at micromolar (μM) concentrations.
Metabolomics revealed that MINCH induces lipid accumulation in a manner similar to peroxisome proliferator activated receptor gamma (PPARG)-agonist rosiglitazone through upregulation of the pyruvate cycle, which was recently identified as a key driver of de novo lipogenesis. Analysis of the metabolome in the presence of the PPARG-inhibitor GW9662 indicated that the metabolic effects of MINCH are at least partly mediated through a PPARG-independent mechanism.
However, all observed effects of MINCH occurred only at high concentrations (10 μM), which are three orders of magnitude above current plasticiser levels detected in human serum. Overall, the metabolomic assessment of DINCH and MINCH in SGBS cells revealed no adipogenic potential at physiologically relevant concentrations. These findings are consistent with previous in vivo studies and support the use of this approach as a New Approach Method (NAM) for assessing adipogenic effects of environmental chemicals.etabolic effects of MINCH are at least partly mediated through a PPARG-independent mechanism.
This study supports the use of metabolomics as a New Approach Method (NAM) to identify adipogenic effects of environmental chemicals. The absence of effects at physiologically relevant concentrations reinforces the low risk of DINCH and MINCH under current exposure conditions.
Growing evidence suggests that exposure to certain metabolism-disrupting chemicals (MDCs), such as the phthalate plasticizer DEHP, might promote obesity in humans, contributing to the spread of this global health problem. Due to the restriction on the use of phthalates, there has been a shift to safer declared substitutes, including the plasticizer diisononyl-cyclohexane-1,2-dicarboxylate (DINCH). Notwithstanding, recent studies suggest that the primary metabolite monoisononyl-cyclohexane-1,2-dicarboxylic acid ester (MINCH), induces differentiation of human adipocytes and affects enzyme levels of key metabolic pathways. Given the lack of methods for assessing metabolism-disrupting effects of chemicals on adipose tissue, we used metabolomics to analyze human SGSB cells exposed to DINCH or MINCH. Concentration analysis of DINCH and MINCH revealed that uptake of MINCH in preadipocytes was associated with increased lipid accumulation during adipogenesis. Although we also observed intracellular uptake for DINCH, the solubility of DINCH in cell culture medium was limited, hampering the analysis of possible effects in the μM concentration range. Metabolomics revealed that MINCH induces lipid accumulation similar to peroxisome proliferator-activated receptor gamma (PPARG)-agonist rosiglitazone through upregulation of the pyruvate cycle, which was recently identified as a key driver of de novo lipogenesis. Analysis of the metabolome in the presence of the PPARG-inhibitor GW9662 indicated that the effect of MINCH on metabolism was mediated at least partly by a PPARG-independent mechanism. However, all effects of MINCH were only observed at high concentrations of 10 μM, which are three orders of magnitudes higher than the current concentrations of plasticizers in human serum. Overall, the assessment of the effects of DINCH and MINCH on SGBS cells by metabolomics revealed no adipogenic potential at physiologically relevant concentrations. This finding aligns with previous in vivo studies and supports the potential of our method as a New Approach Method (NAM) for the assessment of adipogenic effects of environmental chemicals.