The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently published as an OECD Test Guideline for detecting chemicals acting on the thyroid axis. However, the OECD validation did not cover all ...mechanisms that can potentially be detected by the XETA. This study was therefore initiated to investigate and consolidate the applicability domain of the XETA regarding the following mechanisms: thyroid hormone receptor (THR) agonism, sodium-iodide symporter (NIS) inhibition, thyroperoxidase (TPO) inhibition, deiodinase (DIO) inhibition, glucocorticoid receptor (GR) agonism, and uridine 5′-diphospho-glucuronosyltransferase (UDPGT) induction. In total, 22 chemicals identified as thyroid-active or -inactive in Amphibian Metamorphosis Assays (AMAs) were tested using the XETA OECD Test Guideline. The comparison showed that both assays are highly concordant in identifying chemicals with mechanisms of action related to THR agonism, DIO inhibition, and GR agonism. They also consistently identified the UDPGT inducers as thyroid inactive. NIS inhibition, investigated using sodium perchlorate, was not detected in the XETA. TPO inhibition requires further mechanistic investigations as the reference chemicals tested resulted in opposing response directions in the XETA and AMA. This study contributes refining the applicability domain of the XETA, thereby helping to clarify the conditions where it can be used as an ethical alternative to the AMA.
•The Xenopus Eleutheroembryonic Thyroid Assay (XETA) was recently developed to screen for thyroid activity of chemicals.•XETA results were compared to Amphibian Metamorphosis Assay (AMA) outcomes for the detection of thyroid-active chemicals.•Results were concordant for all selected mechanisms, but the XETA did not detect inhibition of the sodium-iodide symporter.•Thyroperoxidase inhibition requires further mechanistic investigations due to equivocal responses in the XETA.•The XETA and the AMA consistently identified uridine 5′-diphospho-glucuronosyltransferase inducers as thyroid-inactive.
The goal of PrecisionTox is to overcome conceptual barriers to replacing traditional mammalian chemical safety testing by accelerating the discovery of evolutionarily conserved toxicity pathways that ...are shared by descent among humans and more distantly related animals. An international consortium is systematically testing the toxicological effects of a diverse set of chemicals on a suite of five model species comprising fruit flies, nematodes, water fleas, and embryos of clawed frogs and zebrafish along with human cell lines. Multiple forms of omics and comparative toxicology data are integrated to map the evolutionary origins of biomolecular interactions that are predictive of adverse health effects, to major branches of the animal phylogeny. These conserved elements of adverse outcome pathways (AOPs) and their biomarkers are expected to provide mechanistic insight useful for regulating groups of chemicals based on their shared modes of action. PrecisionTox also aims to quantify risk variation within populations by recognizing susceptibility as a heritable trait that varies with genetic diversity. This initiative incorporates legal experts and collaborates with risk managers to address specific needs within European chemicals legislation, including the uptake of new approach methodologies (NAMs) for setting precise regulatory limits on toxic chemicals.
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•PrecisionTox is funded by the EU’s Horizon 2020 programme until the year 2026.•Conserved toxicity pathways will be identified across five model organisms and humans.•Artificial intelligence will reveal adverse outcome pathways and their biomarkers.•Quantitative genetics is used to examine susceptibility to toxicity as a variable trait.•Collaboration with policy makers facilitates use of biomarkers for safety assessment.
