Development of computer models to predict chemicals interference with thyroid hormones

Marianne Dybdahl

There is a growing concern about chemicals that may interfere with the body’s hormone systems and cause harmful effects. So far most focus has been on chemicals that alter the balance of sex hormones, but interference with thyroid hormones is now receiving increasing attention. Besides their function in energy metabolism, thyroid hormones play an important role during early brain development. Even moderate and transient reductions in maternal hormone levels during pregnancy can adversely affect the child’s neurological development.

Chemicals may interfere with the thyroid hormones in many different ways, such as altering the production of the hormones, or altering their transport and metabolism in the body. A battery of different test methods is therefore needed to study the potential effects of chemicals, and this is a very resource-consuming task for the many thousands of untested chemicals.

To facilitate this task, computer models have become an important tool to screen and prioritize chemicals for further experimental testing, thereby reducing costs and number of test animals. At DTU Food we are using computer models to predict health effects of chemicals based on their molecular structure. The models are so-called QSARs (quantitative structure-activity relationships).

The aim of the project is to develop computer models for some of the many mechanisms underlying interference with thyroid hormones. To build the models, we will e.g. use experimental test data obtained through collaboration with the US Environmental Protection Agency.

The developed models will be used to screen more than 600,000 chemicals, including around 70,000 chemicals available at the European market. The resulting predictions will be made freely available in an online database. Such a virtual screening may in a fast and cost-efficient way identify potential thyroid hormone disrupting chemicals in our food, environment and consumer products. The new models can also contribute to future design of safer chemicals and drugs.

Project status November 2017

Besides their function in energy metabolism, thyroid hormones play an important role during early brain development. Even moderate and transient reductions in maternal hormone levels during pregnancy can adversely affect the child’s neurological development. The aim with the present project was to develop computer models for some of the most important mechanisms known to disturb the hormone balance.
The models are so-called QSARs (quantitative structure-activity relationships), that can predict effects of chemicals based on their molecular structure. To build the models, we have used experimental test data obtained through collaboration with US partners.

Results: A number of QSAR models covering different mechanisms have been developed and validated. The models can predict if chemicals can interfere with the synthesis and metabolism of the hormones.
The developed models have been used to screen around 70,000 REACH chemicals, i.e. chemicals potentially available at the European market. In this way, knowledge from experimental data on a limited number of chemicals was used to generate information for 10,000s of untested chemicals. The predictions will be made freely available in the QSAR database at DTU Food.

Conclusion: The models can in a fast and cost-efficient way identify potential hormone disrupting chemicals in our food, environment and consumer products. The new models can also contribute to future design of safer chemicals and drugs.

Results from the project was published recently in Computational Toxicology 2017; 1:39-48 and Computational Toxicology 2017; 4:11-21. The results are also included in a PhD report: http://orbit.dtu.dk/files/137601994/PhD_afhandling_Sine_Rosenberg_print.pdf

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