Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals—The ATHENA Project
Abstract
:1. Introduction
2. Results
2.1. Terminology, Concept and Rationale
- The development of quantitative structure–activity relationships (QSARs) for molecular initiating events leading to diminished TH action, to allow for the improved screening of candidate TH system disruptors;
- The scaling up of in vitro methods for the inhibition of deiodinases, dehalogenases and cell membrane TH transporters to a high throughput format;
- The development of new assays to capture the disruption of the delivery of THs across physiological barriers (cell membrane transporters in the blood–brain barrier, the blood–cerebrospinal fluid barrier, and the placenta);
- The development of new assays based on human pluripotent stem cell-derived brain cells and brain organoids to complement and, to a certain extent, replace current animal models;
- The identification of endpoints reflective of brain morphology and markers of brain development for possible inclusion in existing Organisation for Economic Co-operation and Development (OECD) test guidelines;
- The integration of new and existing test methods into a coherent testing strategy;
- The validation of the human relevance of new test methods.
2.2. Regulatory and Societal Needs for New Test Methods for Thyroid Hormone System Disruption
2.3. Overall Approach and Methodology
- Domain 1: Mobilising basic research for the development of novel assays for TH system disruption;
- Domain 2: The development of test methods towards assay pre-validation and ring-testing;
- Domain 3: Testing strategies and testing in a multi-causal context;
- Domain 4: Enhanced international collaboration and development of international strategies for TH system disruptor identification and regulation.
2.3.1. Domain 1: Mobilising Basic Research for the Development of Novel TH System Disruption Assays
2.3.2. Domain 2: Development of Test Methods towards Assay Pre-Validation and Ring-Testing
2.3.3. Domain 3: Thyroid Hormone System Disruptor Testing in a Multi-Factorial Context and the Development of Comprehensive Testing Strategies
2.3.4. Enhanced International Collaboration, Development of International Strategies for TH System Disruptor Identification and Regulation
3. Discussion
- Show adverse effects in an intact organism or its progeny, which is a change in the morphology, physiology, growth, development, reproduction or life span of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;
- Have an endocrine mode of action (MOA), i.e., alter the function(s) of the endocrine system;
- Exhibit adverse effects because of an endocrine MOA.
- Substances inducing histopathological changes in the thyroid (focal hyperplasia and/or neoplasia), with or without changes in the circulating levels of TH, are regarded as posing a hazard for human TH insufficiency in adults, as well as the pre- and post-natal neurological development of offspring;
- Substances that alter circulating levels of T3 and/or T4 without histopathological findings are also seen as presenting a potential concern for neurodevelopment;
- In the absence of substance-specific data which provide proof of the contrary, humans and rodents are considered equally sensitive to TH system disruption (including cases where liver enzyme induction is responsible for increased TH clearance).
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AOP | Adverse Outcome Pathway |
DIO | Deiodinase |
ECHA | European Chemicals Agency |
ECVAM | European Centre for the Validation of Alternative Methods |
EFSA | European Food Safety Authority |
EOGRTS | Extended One-Generation Reproductive Toxicity Study |
HTS | High Throughput Screening |
EROD | 7-Ethoxyresorufin O-dealkylase |
IYD | Iodotyrosine dehalogenase 1 |
MCT8 | Monocarboxylate transporter 8 |
MOA | Mode of Action |
NIS | Sodium iodide symporter |
OECD | Organisation for Economic Cooperation and Development |
PROD | Pentoxyresorufin O-dealkylase |
QSAR | Quantitative Structure–Activity Relationship |
T3 | Triiodothyronine |
T4 | Thyroxine |
TBG | Thyroxin-Binding Globulin |
TG | Test Guideline |
TR | Thyroid Receptor |
TRH | Thyrotropin-Releasing Hormone |
TSH | Thyroid Stimulating Hormone |
TSHR | Thyroid Stimulating Hormone Receptor |
TTR | Transthyretin |
UDPGT | Uridine 5′diphospho-glucuronosyltransferase |
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Share and Cite
Kortenkamp, A.; Axelstad, M.; Baig, A.H.; Bergman, Å.; Bornehag, C.-G.; Cenijn, P.; Christiansen, S.; Demeneix, B.; Derakhshan, A.; Fini, J.-B.; et al. Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals—The ATHENA Project. Int. J. Mol. Sci. 2020, 21, 3123. https://doi.org/10.3390/ijms21093123
Kortenkamp A, Axelstad M, Baig AH, Bergman Å, Bornehag C-G, Cenijn P, Christiansen S, Demeneix B, Derakhshan A, Fini J-B, et al. Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals—The ATHENA Project. International Journal of Molecular Sciences. 2020; 21(9):3123. https://doi.org/10.3390/ijms21093123
Chicago/Turabian StyleKortenkamp, Andreas, Marta Axelstad, Asma H. Baig, Åke Bergman, Carl-Gustaf Bornehag, Peter Cenijn, Sofie Christiansen, Barbara Demeneix, Arash Derakhshan, Jean-Baptiste Fini, and et al. 2020. "Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals—The ATHENA Project" International Journal of Molecular Sciences 21, no. 9: 3123. https://doi.org/10.3390/ijms21093123