ENDpoiNTs - Novel testing methods for endocrine disruption linked to developmental neurotoxicity
The European Union Horizon 2020 research and innovation project ENDpoiNTs develops novel testing and screening methods to identify endocrine-disrupting chemicals (EDCs) that induce human developmental neurotoxicity (DNT). There is strong evidence supporting associations between EDC exposure and impaired neurodevelopment. However, regulatory guidelines for the hazard assessment of EDCs do not cover DNT. One reason is the lack of scientific knowledge on how endocrine disruption (ED) is linked to DNT. Thus, there is an urgent need for novel testing and screening tools to address ED-induced DNT, based on new scientific knowledge. In ENDpoiNTs, we develop a testing battery of in vivo, in vitro, and in silico models to test and screen chemicals for endocrine-disrupting properties impacting human neurodevelopment. Finally. these methods shall be integrated into European and international chemical regulatory frameworks. The project concept is based on two pillars:
- Module 1: Test method development. Establishment of correlative and causal links between the modulation of endocrine pathways and DNT endpoints.
- Module 2: Human & regulatory relevance of the developed test methods. Establishment of human relevance by linking experimental and epidemiological evidence and regulatory impact by continuous interaction with stakeholders.
ONTOX – ONTology-driven and artificial intelligence-based repeated dose TOXicity testing of chemicals for next generation risk assessment
The vision of the ONTOX consortium is to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21st century toxicity testing and next generation risk assessment. ONTOX will deliver a generic strategy to create innovative new approach methodologies (NAMs) addressing adversities in the liver (steatosis and cholestasis), kidneys (tubular necrosis and crystallopathy), and developing brain (neural tube closure and cognitive function defects) induced by a variety of chemicals. Each NAM will consist of a computational system based on cutting-edge artificial intelligence (AI) and will be primarily fed by available biological/mechanistic, toxicological/epidemiological, physico-chemical and kinetic data. Data will be consecutively integrated in physiological maps, quantitative adverse outcome pathway networks, and ontology frameworks. Data gaps, as identified by AI, will be filled by targeted state-of-the-art in vitro and in silico testing. NAMs will be used to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. They will be evaluated and applied in collaboration with industrial and regulatory stakeholders in order to maximize end-user acceptance and regulatory confidence. ONTOX is funded by the European Union research and innovation funding programme Horizon 2020.
European partnership for the assessment of risks from chemicals (PARC)
The Horizon Europe project “European partnership for the assessment of risks from chemicals (PARC)”, funded by the European Commission, aims to shape the methodological landscape of chemical risk assessment in Europe for the next decade. With more than 200 partners from all over Europe and a budget of €400 million, PARC is one of the largest projects of its kind in the world. Between 2022 and 2027, the working group Fritsche will contribute to the work package 5, which overall goal is to focus on hazard assessment for human and environmental health in three different directions: fill data gaps identified by key stakeholders, develop and/or improve methodologies for hazard assessment to progress towards next generation risk assessment (NGRA).
NTP Screening project
The US National Institute of Environmental Health Sciences (NIEHS) Division of the National Toxicology Program (DNTP) has identified developmental neurotoxicity (DNT) and the increase in neurodevelopmental disorders as a societal health risk. Chemical exposure is thereby considered a relevant risk factor and the DNTP wants to better understand how chemicals trigger DNT. Therefore the DNTP commissioned the testing of 115 chemicals in new approach methods that are based on alternative model organisms (e.g. zebrafish) or cell-based methods. In this project, we test the set of 115 chemicals in the human “Neurosphere Assay”. The assay is based on human neural progenitor cells that are grown in three-dimensional spheroids and it represents several key processes of human brain development, namely, cell proliferation, migration, neuronal differentiation and morphology as well as oligodendrocyte differentiation. The assay is applied in a semi-automated medium-throughput set-up and can identify the potential of a chemical to disturb any of the aforementioned processes. This project is funded by the National Toxicology Program (NTP).
More information: https://ntp.niehs.nih.gov/
CEFIC-LRI-AIMT11: Enhancing in vitro DNT testing strategy
In light of the necessity to refine the existing test methods for the assessment of developmental neurotoxicity (DNT) of chemicals, a DNT in vitro battery (DNT-IVB) has recently been assembled under the supervision of the European Food Safety Authority (EFSA). Despite its extensive coverage of neurodevelopmental key events, the current DNT-IVB mainly focuses on neurons and oligodendrocytes. By implementing endpoints based on radial glial cells, astrocytes, and microglia, we aim to further improve the predictivity and performance of the current test battery. The project is being carried out in cooperation with the research group of Prof. Marcel Leist at the University of Konstanz and funded by the Long-Range Research Initiative (LRI) Programme of the European Chemical Industry Council (CEFIC).
RTG2578 – Project 1c: Investigations on DNA repair capacities of human neural progenitor cells (NPC) depending on the degree of differentiation and cell type
The Research Training Group (RTG) 2578 combines expertise in toxicology and stem cell research to study the impact of genotoxins on the differentiation efficacy of murine and human stem and progenitor cells and the functional competence of thereof derived differentiated progeny. In the subproject 1c, we analyze the impact of genotoxins with different modes-of-action on human brain development, by focusing on the DNA damage response and repair capacity during different developmental time points and cell types. The project is funded by the Funded by the German Research Foundation (DFG).
Establishment of human induced pluripotent stem cell (hiPSC)-based assays for testing for developmental immunotoxicity in vitro
The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be much more susceptible to chemical perturbations than that of the adult and hence the effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Furthermore, the majority of regulatory agencies worldwide do not routinely require developmental immunotoxicity (DIT) testing for chemicals and pharmaceuticals. DIT studies are resource-intensive as they take almost one year, produce high costs and use a large number of animals. Moreover, developmental differences in immune system development are evident among species compared to humans, making extrapolation from rodents to humans difficult. Therefore, the aim of this project is to take a first step on the road to the development of a human cell-based in vitro DIT battery using hiPSC-based development of the different immune cells covering the following aspects of the developing immune system: (i) primitive hematopoiesis and (ii) definite hematopoiesis towards the T-cell lineage. The newly established assays will then be used to test compounds for their DIT potential. The project is sponsored by Clariant AG, Schweiz.
For more information please visit: https://www.leibniz-alternatives.de/
Cross-species characterisation of the molecular and cellular effects of thyroid hormones on the development of neural progenitor cells in vitro
Thyroid hormones (TH), thyroxine (T4) and the more active 3,3',5-triiodothyronine (T3) are indispensable for normal brain development and can influence numerous neurodevelopmental processes. However, there is a profound data gap on understanding of TH transport and specific TH action within individual brain cell types. Within this project, we are using e.g. single cell RNA sequencing to investigate the cell type-specific regulation of TH-dependent genes in a species-specific context. The aim is to gain understanding of the molecular and cellular effects as well as the distribution kinetics of TH in human and rat neurospheres with the final goal of in silico modulation of TH transport and molecular as well as cellular TH actions. Using existential in vivo rat data, this project allows quantitative in vitro to in vivo extrapolation (QIVIVE) resulting in a quantitative Adverse Outcome Pathway (AOP) network concerning brain development. The project is funded by Syngenta United Kingdom Limited - Jealott’s Hill International Research Centre.