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Physiologically-Based Pharmacokinetic (PBPK) Model for the Thyroid Hormones in the Pregnant Rat and Fetus.
Citation:
El-Masri, H., M. Jasper, AND M. Gilbert. Physiologically-Based Pharmacokinetic (PBPK) Model for the Thyroid Hormones in the Pregnant Rat and Fetus. Society of Toxicology, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
During early gestation, the developing fetus relies on the maternal supply of thyroid hormones (THs). Therefore, economy of maternal THs during pregnancy is tightly regulated to provide sufficient supply of THs to fetal tissues for normal development. In this work, the physiological processes of THs secretion, transport, distribution, diffusion into tissue, activation and deactivation by deiodinases, and metabolic clearance were included into the developmental physiologically based pharmacokinetic model for the rat. The PBPK model is used to quantitatively describe the tissue economy of THs in the pregnant rat and fetus. Utility of this PBPK model will enable the assessment of 1) the impact of chemical exposure on alteration of THs levels during gestation and 2) the relationships between serum TH alterations and TH-dependent neurodevelopmental impartment.
Description:
A developmental PBPK model is constructed to quantitatively describe the tissue economy of the thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), in the rat. The model is also used to link maternal (THs) to rat fetal tissues via placental transfer. THs are important for development and growth. During early gestation, the developing fetus relies on the maternal supply of T4. Therefore, economy of maternal THs during pregnancy is tightly regulated to provide sufficient supply of THs to fetal tissues for normal development. Regulation of THs relies on the function of the hypothalamic-pituitary-thyroid axis, while THs tissue economy is modulated by a complex system of hormone transport over membranes and enzymatic activation and inactivation by the iodothyronines and other metabolizing enzymes. Biological activity of the THs is primarily mediated by T3, which is produced from T4. However, the tissue content of T3 and T4 is balanced by activity of three types of deiodination enzymes. These enzymes are distinguished by their tissue distribution, physiological roles, affinity for substrate, and metabolites they form. In this work, the physiological processes of THs secretion, transport, distribution, diffusion into tissue, activation and deactivation by deiodinases, and metabolic clearance were included into the developmental physiologically based pharmacokinetic model for the rat. The PBPK model is used to quantitatively describe the tissue economy of THs in the pregnant rat and fetus. Utility of this PBPK model will enable the assessment of 1) the impact of chemical exposure on alteration of THs levels during gestation and 2) the relationships between serum TH alterations and TH-dependent neurodevelopmental impartment. Disclaimer: This abstract represents the opinion of the authors and does not necessarily reflect U.S. EPA policy.