Endocrine Abstracts

The thyroid hormone system (THS) is a main target of endocrine-disrupting chemicals (EDC), natural or human-made chemicals that may interfere with hormonal systems during development, adolescence or adulthood. EDC interference, especially during sensitive developmental windows of susceptibility, may lead to irreversible setpoint changes of hormonal feedback regulation, inadequate function of hormone-regulated processes or predispose to disease development in adulthood or subsequent generations. Human, especially, brain development critically depends on adequate provision of maternal T4, particularly during first trimester fetal thyroid development and maturation, lessons learned from impact of iodide deficiency and genetic disorders affecting development and function of the THS. In silico, in vitro, in vivo test systems and animal experimental models allow the systematic, hypothesis-free or targeted interrogation of potential interference of single or groups of chemicals with relevant functional components of the THS system. ~70 000 low molecular weight chemicals, representing 1/5 of the current chemical universe, were screened for five THS targets (hr DIO1-3, DEHAL1, MCT8) of EDC using non-radioactive high throughput screening assays photometrically detecting iodide by the Sandell-Kolthoff reaction. Identified inhibitors are further prioritized with respect to their potency, target specificity, cytotoxicity and potential biological, medical or environmental relevance. Prioritized chemicals undergo testing in selected (established, validated, novel) in vitro test methods (reporter assays, cellular models, organoids) applicable for regulatory purposes by comparison with reference compounds affecting the respective THS target. Top hits are functionally characterized in vivo using mechanistically meaningful and biologically-informative experimental models for living organisms, which reflect intact function and regulation of the THS during and/or after completion of development (Xenopus amphibian metamorphosis, zebrafish, rodent). Application of 3R principles, development of New Approach Methodologies (NAM), and such data-based focused in vivo testing for prioritized relevant chemicals will accelerate EDC characterization, increase hazard-predictive power and chemicals safety for environmental and human health.

References: 1.doi: 10.3390/ijms21093123; doi: 10.1016/j.beem.2021.101562; doi: 10.12688/openreseurope.18739.1.

Funding support : EU Horizon 2020, ATHENA project, # 825161 & DFG TRR 296/1 2020, P16, # 424957847.