In silico analysis decodes transthyretin (TTR) binding and thyroid disrupting effects of per- and polyfluoroalkyl substances (PFAS)

Abstract

Transthyretin (TTR) is a homo-tetramer protein involved in the transport of thyroid hormone (thyroxine; T4) in the plasma and cerebrospinal fluid. Many pollutants have been shown to bind to TTR, which could be alarming as disruption in the thyroid hormone system can lead to several physiological problems. It is also indicated that the monomerization of tetramer and destabilization of monomer can lead to amyloidogenesis. Many compounds are identified that can bind to tetramer and stabilize the tetramer leading to the inhibition of amyloid fibril formation. Other compounds are known to bind tetramer and induce amyloid fibril formation. Among the pollutants, per- and polyfluoroalkyl substances (PFAS) are known to disrupt the thyroid hormone system. The molecular mechanisms of thyroid hormone disruption could be diverse, as some are known to bind with thyroid hormone receptors, and others can bind to membrane transporters. Binding to TTR could also be one of the important pathways to alter thyroid signaling. However, the molecular interactions that drive thyroid-disrupting effects of long-chain and short-chain PFASs are not comprehensively understood at the molecular level. In this study, using a computational approach, we show that carbon chain length and functional group in PFASs are structural determinants, in which longer carbon chains of PFASs and sulfur-containing PFASs favor stronger interactions with TTR than their shorter-chained counterparts. Interestingly, short-chain PFAS also showed strong binding capacity, and the interaction energy for some was as close to the longer-chain PFAS. This suggests that short-chain PFASs are not completely safe, and their use and build-up in the environment should be carefully regulated. Of note, TTR homologs analysis suggests that thyroid-disrupting effects of PFASs could be most likely translated to TTR-like proteins and other species.

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

“…PFASs with a medium chain length and a sulfonate acid group preferentially bind to TTR, while those with chain lengths longer than 12 carbons prefer TBG binding . Some long-chain PFASs, such as PFDoDA, PFUnDA, and perfluorooctanoic acid (PFOA), have been found to strongly interact with blood TTR and show higher toxicity propensity in silico analysis . The binding between PFASs and TTR is driven by hydrogen bonds and hydrophobic interactions, with hydrophobic interactions being the major contributors .…”

“…194 The binding between PFASs and TTR is driven by hydrogen bonds and hydrophobic interactions, with hydrophobic interactions being the major contributors. 194 Recent research has also proposed a model to quantitatively evaluate the relationship between TTR-binding chemicals, including PFASs, and FTHs in vivo. The study revealed that the levels of FT4 and FT3 in circulation are affected to different degrees in both general population and individuals with occupational exposure to various TTR-binding chemicals, including hydroxylated PCBs (OH-PCBs), hydroxylated-PBDEs (OH-PBDEs), PFASs, and phenols.…”

“…193 Some long-chain PFASs, such as PFDoDA, PFUnDA, and perfluorooctanoic acid (PFOA), have been found to strongly interact with blood TTR and show higher toxicity propensity in silico analysis. 194 The binding between PFASs and TTR is driven by hydrogen bonds and hydrophobic interactions, with hydrophobic interactions being the major contributors. 194 Recent research has also proposed a model to quantitatively evaluate the relationship between TTR-binding chemicals, including PFASs, and FTHs in vivo.…”

“…230 Phthalates, such as diethyl phthalate, can also strongly interact with blood TTR. 193,194,231 In general, chemicals tend to competitively bind with TTR and TRs, leading to an increase in FTHs levels in circulation. This triggers a negative feedback loop in the HPT axis, ultimately resulting in a decrease in TSH levels.…”

Rafoxanide, a salicylanilide anthelmintic, interacts with human plasma protein transthyretin

“…It has also been shown that several house dust contaminants bind to TTR in a competitive manner with a fluorescent conjugate of T 4 [10]. The bindability of environmental substances to TTR is recognized as a significant issue and potential health hazard [11,12].…”