Linking Transthyretin-Binding Chemicals and Free Thyroid Hormones: In Vitro to In Vivo Extrapolation Based on a Competitive Binding Model

Abstract

Large numbers of pollutants competitively inhibit the binding between thyroid hormones and transthyretin (TTR) in vitro. However, the impact of this unintended binding on free thyroid hormones in vivo has not yet been characterized. Herein, we established a quantitative in vitro to in vivo extrapolation (QIVIVE) method based on a competitive binding model to quantify the effect of TTR-binding chemicals on free thyroid hormones in human blood. Twenty-five TTR-binding chemicals including 6 hydroxyl polybromodiphenyl ethers (OH-PDBEs), 6 hydroxyl polychlorobiphenyls (OH-PCBs), 4 halogenphenols, 5 per- and polyfluorinated substances (PFASs), and 4 phenols were selected for investigation. Incorporating the in vitro binding parameters and human exposure data, the QIVIVE model could well predict the in vivo effect on free thyroid hormones. Co-exposure to twenty-five typical TTR-binding chemicals resulted in median increases of 0.080 and 0.060% in circulating levels of free thyroxine (FT4) and free triiodothyronine (FT3) in the general population. Individuals with occupational exposure to TTR-binding chemicals suffered 1.88–32.2% increases in free thyroid hormone levels. This study provides a quantitative tool to evaluate the thyroid-disrupting risks of TTR-binding chemicals and proposes a new framework for assessing the in vivo effects of chemical exposures on endogenous molecules.

Thyroid Hormone Biomonitoring: A Review on Their Metabolism and Machine-Learning Based Analysis on Effects of Endocrine Disrupting Chemicals

“…As early as 1999, it was found that OH-PCBs exhibited TH-like affinity to serum TTR in vitro , suggesting a potential inhibition of TH transport in vivo . Quantitative models also showed that OH-PCBs may competitively bind with TTR, resulting in aggregation of FTHs . The presence of OH-PCBs also suppressed T3-induced transcriptional activation of TRs and led to aggression of T3 in Japanese macaque ( Macaca fuscata ) .…”

Identification of Hydrocarbon Sulfonates as Previously Overlooked Transthyretin Ligands in the Environment

“…Disruption of normal THs levels in serum can impact the development of the central nervous system, especially during fetal development, and is associated with neurological disorders including Alzheimer’s disease (AD) . Epidemiological studies have revealed an association between exposure to thyroid hormone disrupting chemicals (TDCs) and the increased risk of thyroid-related diseases. − Transthyretin (TTR) is a major thyroxine (T 4 ) transport protein in serum that has been demonstrated to mediate the toxicity of many TDCs. , TDCs can compete with endogenous T 4 for binding to TTR, which can lead to the increased clearance of free T 4 and the disruption of TH homeostasis. − In addition to TH disruption, binding to TTR can also mediate the transport of chemical pollutants across placental and blood–brain barriers into various compartments ( e.g., fetus and brain), which may induce a multitude of adverse effects. − Thus, the identification of environmental chemicals binding to TTR is important for understanding their potential health risks.…”

“…5−7 Transthyretin (TTR) is a major thyroxine (T 4 ) transport protein in serum that has been demonstrated to mediate the toxicity of many TDCs. 8,9 TDCs can compete with endogenous T 4 for binding to TTR, which can lead to the increased clearance of free T 4 and the disruption of TH homeostasis. 9−11 In addition to TH disruption, binding to TTR can also mediate the transport of chemical pollutants across placental and blood−brain barriers into various compartments (e.g., fetus and brain), which may induce a multitude of adverse effects.…”

Tox24 Challenge

“…Specifically, displacement of TH from TTR may result in reduced delivery of TH to target tissue and disruption of pathways dependent on TH activation . TH displaced from TTR may also be metabolized and excreted resulting in decreased serum TH levels . Due to the limited amount of data on binding activities of compounds to TTR, only a few computational studies are reported in the literature.…”

“…This data set has been split into a training set (1012 compounds) as well as leaderboard set (200 compounds) and a blind set (300 compounds). The compounds from previous studies ,, that overlapped with molecules in the challenge data set were mainly used as part of the training set. It should be mentioned that some compounds are mixtures, while others are salts, and some contain metals.…”