OR19-4 A Minimal Human Physiologically Based Kinetics Model of Thyroid Hormones and Effects of Endocrine-Disrupting Chemicals

Abstract

Abstract Thyroid hormones (THs) thyroxine (T4) and triiodothyronine (T3) are under homeostatic and circadian control by the hypothalamic-pituitary-thyroid axis while their free plasma concentrations are strongly buffered by three TH binding proteins (THBPs): thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB). The THBPs are crucial to the even delivery of THs from the blood to tissues, but their relative contributions and spatial kinetics within tissues are unclear. Many endocrine-disrupting chemicals (EDCs) can interfere with the regulation and actions of THs, some of which are structurally similar to THs with comparable or even higher binding affinities for THBPs. It has been suspected that by disrupting the binding of THs with THBPs, EDCs may alter the plasma TH concentrations and the delivery to tissues. Given that the majority of the binding sites on THBPs are unoccupied—thus available for EDC binding—it is uncertain whether TH homeostasis can be tangibly perturbed by EDC exposure. To answer these questions, we constructed a spatial multi-compartment human physiologically based kinetic (PBK) model of TH production, distribution, and metabolism. The model contains the thyroid, liver, and rest-of-body compartments with explicit descriptions of the reversible binding kinetics between THs and THBPs in the blood. The model was parameterized and validated extensively based on literature data. Here we reported several novel findings: (1) The contribution to TH tissue delivery by each THBP is not spatially constant across a tissue: ALB always contributes more THs to the arterial side of the tissue while TBG contributes more to the venous side. (2) THBPs are essential for a uniform TH tissue delivery but are cross-compensatory in this role. (3) Contrary to the long-held assumption that ALB is the dominant contributor, TBG contributes more of the THs delivered to a tissue overall than ALB and TTR. (4) Bode plot analysis using control theory suggests that a circadian signal driving T4-to-T3 conversion in the extra-thyroidal tissue is crucial to establish the distinct phase and amplitude profiles of circulating T3 and T4 in humans. (5) Displacement of THs from THBPs by high-affinity EDCs has a negligible effect on free plasma THs even under high exposures. (6) Daily exposure to THBP-binding EDCs does not affect the circadian variations in tissue delivery of THs. The PBK model can be further elaborated in the future to make tissue-specific predictions of TH kinetics. Presentation: Monday, June 13, 2022 11:45 p.m. - 12:00 p.m.