Cyprotex have recently published an account of an innovative project to study the effects on human health of exposure to disrupters of thyroid hormone (TH) synthesis with colleagues in academia and industry from six European countries. A state of the art integrated screening platform is under development, comprising novel three-dimensional (3D) in vitro thyroid constructs housed in a modular microfluidic bioreactor. The temporal response to putative thyroid disrupters will be monitored by means of real-time measurements of key biochemical changes and TH synthesis. Comprehensive unbiased and targeted proteomic and genomic analysis will complete the data package to be generated for each test compound. The thyroid constructs will be able to utilise cells from male and female thyroids, enabling the responses to thyroid disrupters to be determined in a sex-specific manner.
The role of the Modelling and Simulation (M&S) group at Cyprotex is to predict the health outcomes that are to be expected in vivo from exposure to TH synthesis disrupters. Predictions will be made by means of a computational simulation model, utilising data generated from the screening platform, but also taking account of:
- Route, amount and duration of exposure, and the toxicokinetics of the compounds to be studied.
- Physiological regulation of thyroid gland function.
- Response of peripheral tissues to circulating TH concentrations.
The exposure to compounds together with their toxicodynamics determines the concentrations to which the thyroid gland is actually exposed in vivo. TH synthesis within the thyroid gland functions within a tightly-regulated multi-level negative feedback loop involving the hypothalamus and the anterior pituitary gland, mediated via thyrotropin-releasing hormone (TRH) and thyroid stimulating hormone (TSH or thyrotropin). TSH secretion is modulated in a diurnal cycle by the suprachiasmatic nucleus of the hypothalamus, such that the entire system (TSH, and the thyroid hormones T3 and T4), naturally fluctuates over a 24h cycle. Any effects of thyroid disrupting chemicals have to manifest themselves within this cycle. Finally, the peripheral tissues respond in an intrinsically non-linear manner to changes in the circulating concentrations of T3 and T4.
Data and modelling results will be combined to identify key events in the aetiology of adverse health effects caused by thyroid disrupting chemicals, and those key events at the different levels of biological organisation will be linked to define adverse outcome pathways (AOPs) for their overall effects. It is expected that the project will contribute significantly to our understanding of the impact of thyroid-disrupting chemicals on human health.
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The project is funded by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 825745.