Endocrine Abstracts

Current strategies for identifying substances that adversely affect the thyroid hormone (TH) system (e.g. endocrine disrupting compounds [EDC]) are exclusively focussed on changes in serum TH concentrations and thyroid histopathology. This is based on the assumption that altered TH concentrations in serum directly result in impaired TH action in tissues. However, TH action is also regulated by hormone transport into cells and tissues (e.g. MCT8), activation of T4 to T3 by deiodination (DIO1-3), iodine recycling (DEHAL1), and interaction of T3 with TRs isoforms. Therefore, an analysis of EDC effects based on serum analysis and thyroid histopathology is insufficient and needs to be extended. Evaluation of the large number of chemicals for their thyroid hormone system disrupting (THSD) potential requires high-throughput screening (HTS) tests for rapid characterization of human and ecosystem hazards. In addition, a panel of reference chemicals and data describing their bioavailability and bioactivity for specific molecular targets, cellular pathways, and biological processes is needed. Such reference panels need to be validated by in vitro assays and integrated into regulatory test guidelines in order to increase confidence in the predictive value of hazard identification by in vitro methods. We developed a robust HTS platform for MCT8, DIO2, DIO3 and DEHAL1, based on the versatile Sandell-Kolthoff-Reaction to identify causal relationships for chemicals that have thyroid hormone system-mediated (adverse)effects. In total, we screened more than 40,000 compounds for each of the targets and were able to detect drugs, pesticides, and novel chemicals as potential THSD compounds. The versatile HTS platform is an ideal tool to define the causal relationships of a chemical that has thyroid hormone-dependent effects, to identify further research needs of these effects, to prioritize the multitude of substances/chemicals that should be further investigated, and to support regulatory decision making without having to resort to animal-based methods.