The Interaction Study Of New Disinfection By-products,Halogenated Thiophenol Binding To Transthyretin

Increasing concern is being shown about endocrine-disrupting chemicals?EDCs?that are adversely affecting human health and environmental safety.EDCs could influence the normal function of human thyroid system by several mechanisms.Among them,disrupting the thyroid hormone transport proteins is one of the important mechanism of action.Transthyretin?TTR?is one of the blood proteins responsible for thyroxine transport in the biological body.Evaluating the binding potency and interaction mechanism of EDCs to TTR,can facilitate to constructing a virtual method to screen potential thyroid disrupting chemicals.At present,among the more than 140,000 commercial compounds,only about 300 compounds evaluated their potential TTR disrupting effects,indicating most of the chemical substances have not been evaluated,and we are exposed to these potential hazards all the time.Therefore,screening out the substances with potential TTR disruptors is of great important for protecting the human health.Previous studies have shown that halogenated phenolic compounds have high TTR affinity.Except of halogen groups,what are the effects of other substituents on the binding potency between phenolic substances and TTR?The phenolic hydrosulphonyl group has similar properties to the phenolic hydroxyl group,so what is the binding affinity between compounds with phenolic hydrosulphonyl group in their molecular structures and TTR?In this study,fluorescence competition method integrated with computational toxicology methods was used to investigate the interaction of new phenolic disinfection by-products,halogenated thiophenols with human TTR?hTTR?.The main results are as follows:In recent 5 years,the phenolic disinfection byproducts?Phenolic-DBPs?as one groups of emerging disinfection byproducts were widely detected from drinking water,swimming pool water,aquaculture wastewater,and so on.Limited studies have shown that Phenolic-DBPs exhibited greater biological toxicity compared with traditional aliphatic disinfection byproducts.Therefore,further study on the toxic effects of Phenolic-DBPs is important for controlling such pollutants.Except for halogen,there are other substituent groups such as-CHO,-COOH,-NO₂ in the aromatic ring of Phenolic-DBPs.In view of the molecular structure,the phenolic-DBPs may be potential hTTR binders.In this study,five groups of 17typical Phenolic-DBPs were selected as model compounds,including 2,4,6-trihalophenol,2,6-dihalo-4-nitrophenol,3,5-dihalo-4-hydroxybenzaldehyde,halogenated salicylic acid,3,5-dihalo-4-hydroxybenzoic acid.The results showed that 2,4,6-trihalophenol,2,6-dihalo-4-nitrophenol and 3,5-dihalo-4-hydroxybenzaldehyde are high potency hTTR disruptors.TTR binding ability of some halophenols and halonitrophenols was even stronger than that of T4.Phenolic-DBPs with higher number of halogen atoms in their molecular structure had stronger hTTR binding affinity,and the rank of contribution of halogen species to the hTTR of Phenolic-DBPs is:-I>-Br>-Cl.In addition,the substituents effects on the interaction of organic compounds binding to hTTR were also investigated.The results indicated that the hTTR binding affinity of chemicals with electron-withdrawing groups on their structures are higher than that of chemicals with electron donor groups.The results of molecular simulations indicate that ion pair,hydrogen bonding and hydrophobic interaction are the critical noncovalent interaction between Phenolic-DBPs and hTTR.The logarithm of the octanol-water distribution coefficient?LogD?and dipole moment(Dipole_adj)were used as descriptors to construct the QSAR model.The model had goodness of fit,robustness and predictive ability,which can be used to screen other Phenolic-DBPs with potential hTTR binding potency.Thiophenol wastewater is one of industrial waste waters around the world with great harm and extensive pollution,which caused serious pollution to water bodies in the environment and caused great harm to humans.In this study,7 halogenated thiophenols were selected and used to test their hTTR binding affinity and underlying binding mechanism.The results showed that,the tested halothiophenols also had some hTTR binding affinity.The hTTR binding potency of pentachlorothiophenol was stronger than that of T4.The law of halogen species and halogen atom number on the hTTR disrupting effects of halothiophenol was consistent with halogenated phenol compounds.The rank of contribution of the halogen species to the hTTR binding affinity is:-Br>-Cl>-F.The more the number of chlorine atoms,the stronger the hydrophobicity of chlorothiophenol and the hTTR binding affinity is higher.In addition,the hTTR binding affinity of trichloro and pentachlorothiophenol?-SH?is weaker than the corresponding halogenated phenol?-OH?.While,the hTTR binding affinity of monochloro and dichlorothiophenol?-SH?is stronger than corresponding halogenated phenol.Lower ionization degree of the halogenated phenol at low chlorination may be the reason of this phenomenon.The results of molecular simulations indicate that ion pair,hydrogen bonding and hydrophobic interaction are also the critical noncovalent interaction.