An in silico study on human carcinogenicity mechanism of polybrominated biphenyls exposure

• Published in: Chemico-biological interactions 2024-07, Vol.397, p.111075, Article 111075
• Main Authors: Yang, Luze, Sun, Peixuan, Tao, Li, Zhao, Xingmin
• Format: Article
• Language: English
• Subjects: 2D-QSAR; Adverse outcome pathway; Binding Sites; Carcinogens - chemistry; Carcinogens - toxicity; Computer Simulation; Human thyroid cancer; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Molecular docking; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Polybrominated biphenyls; Polybrominated Biphenyls - chemistry; Polybrominated Biphenyls - metabolism; Polybrominated Biphenyls - toxicity; Protein Binding; Quantitative Structure-Activity Relationship; Receptors, Aryl Hydrocarbon - chemistry; Receptors, Aryl Hydrocarbon - metabolism; Thyroid Neoplasms - chemically induced; Thyroid Neoplasms - metabolism; Thyroxine-Binding Globulin - chemistry; Thyroxine-Binding Globulin - metabolism
• ISSN: 0009-2797; 1872-7786; 1872-7786
• DOI: 10.1016/j.cbi.2024.111075

Polybrominated biphenyls (PBBs) are associated with an increased risk of thyroid cancer; however, relevant mechanistic studies are lacking. In this study, we investigated the mechanisms underlying PBB-induced human thyroid cancer. Molecular docking and molecular dynamics methods were employed to investigate the metabolism of PBBs by the cytochrome P450 enzyme under aryl hydrocarbon receptor mediation into mono- and di-hydroxylated metabolites. This was taken as the molecular initiation event. Subsequently, considering the interactions of PBBs and their metabolites with the thyroxine-binding globulin protein as key events, an adverse outcome pathway for thyroid cancer caused by PBBs exposure was constructed. Based on 2D quantitative structure activity relationship (2D-QSAR) models, the contribution of amino acid residues and binding energy were analyzed to understand the mechanism underlying human carcinogenicity (adverse effect) of PBBs. Hydrogen bond and van der Waals interactions were identified as key factors influencing the carcinogenic adverse outcome pathway of PBBs. Analysis of non-bonding forces revealed that PBBs and their hydroxylation products were predominantly bound to the thyroxine-binding globulin protein through hydrophobic and hydrogen bond interactions. The key amino acids involved in hydrophobic interactions were alanine 330, arginine 381 and lysine 270, and the key amino acids involved in hydrogen bond interactions were arginine 381 and lysine 270. This study provides valuable insights into the mechanisms underlying human health risk associated with PBBs exposure. •The adverse outcome pathway of human thyroid cancer caused by PBBs exposure was constructed.•The van der Waals and hydrogen bond interactions were the key factors.•PBBs and their derivatives bound to TBG mainly via hydrophobic and hydrogen bonds.•The key amino acids were Ala330, Arg381 and Lys270.