Periodic Reporting for period 1 - ATHENA (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies)
Berichtszeitraum: 2019-01-01 bis 2020-06-30
The results of experimental work will allow us to construct a network of the thyroid system that can explain how maternal exposure to THDCs can lead to adverse neurodevelopmental effects. It will allow us to formulate a comprehensive testing strategy which will be positioned for international harmonisation to protect against chemicals that are harmful to brain development in foetal life.
• Using existing epidemiological data from two large studies, found that exposure to thyroid system disrupting chemicals in pregnant women is associated with disruption of hypothalamic-pituitary-thyroid axis and exploited these results as a published manuscript (Derakhshan et al Environment International 133 (2019) 105123). There are further manuscripts in preparation.
• Progress in the development of 3D cell models of brain development and neural stem cell division: a human organoid model with a defined panel of neuronal markers covering different stages of maturation and the various cell populations within the organoids, and mouse neurospheres, for which pharmacological assessment of specific TH-dependent endpoints and neural stem cell proliferation has been studied.
• Smaller studies of several thyroid system disrupting compounds have been performed in rats and mice. These studies were dose-selection studies performed to ascertain thyroid hormone system disruption and clarify potential toxicities when compounds were given to pregnant animals. The results from these studies form the basis for large developmental toxicity studies where effects on the thyroid hormone system and brain development will be examined in detail. One major endpoint in these studies will be the formation of heterotopia - the occurrence of misplaced neurons in a defined structure. Heterotopia are linked to thyroid hormone system disruption in rats and in humans they have been correlated to seizure and epilepsy.
• Progress in test method development for a non-radioactive high throughput assay for screening interactions at two non-receptor targets, which has also generated data for QSAR modelling contributing to the development and validation of new QSAR models for inhibition of deiodinases and cell transporter (DIO2, DIO3, DEHAL1 and OATP1C1). A model is also being generated for another transporter (NIS) involved in thyroid hormone synthesis.
• Work has progressed towards robotisation of the Xenopus Eleutheroembryonic Thyroid Assay (XETA), an existing method in the OECD test guidelines. The assay has been refined and validated for medium throughput and will progress to high throughput format. There has also been progress towards development of strategies for establishing the mode of action of THDCs to elucidate their targets in the body and provide information about specific molecular initiating events (MIE).
• Cellular models are being established for study of the disruption of thyroid hormone transport between mother and foetus for placenta, BBB and BCSFB. A placenta perfusion model has also been set up to test transplacental T4 transport to identify the important TH transmembrane transporters that may be inhibited by THDCs. One of these transporters is undergoing development for a nonradioactive high throughput assay to allow screening of inhibitors.
There has been some delay due to the COVID-19 pandemic where in vivo tests, screening and collaborative work had to be postponed due to national lockdowns and restrictions on travel. However, the ATHENA consortium is well positioned to continue to meet the goals of the project, albeit not without a cost-neutral extension.