Mathematical model for thyroid hormone regulation in foetal rat brain

During early pregnancy, significant perturbations to thyroid hormone activity in the mammalian foetal brain can lead to adverse neurodevelopmental outcomes. Endocrine-disrupting chemicals have the potential to cause these perturbations by interfering with normal systemic thyroid hormone regulation. This represents a complex multi-scale problem involving both whole-body (systemic) and tissue-based (local) regulation of thyroid hormones. Understanding whether biological barriers such as the blood-brain barrier and localised transcriptional feedback systems can resist systemic changes in thyroid hormones is critical. We developed a novel mathematical model describing thyroid hormone regulation dynamics in the foetal rat brain and used it to predict the effects of three chemicals (propylthiouracil, sodium phenobarbital, and methimazole) on foetal brain thyroid hormone concentrations. The model predicted changes in foetal brain thyroid hormones within two-fold accuracy based on measured changes in systemic foetal thyroid hormone levels. The model also demonstrates that maternal (dam) systemic thyroid hormone levels can be used to predict these effects during gestation. Mathematical modelling of thyroid hormone regulation in the foetal brain can improve the prediction and understanding of the dynamic effects of endocrine-disrupting chemicals on neurodevelopment and support developmental neurotoxicity risk assessment.