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

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.

Risk mitigation strategy and mechanism analysis of neonicotinoid pesticides on earthworms.

Neonicotinoid insecticides (NNIs) are a new class of widely used insecticides with certain risks to non-target organisms, like earthworms. The gray correlation method was used to calculate the comprehensive risk effect value of acute toxicity (LC50) and bioaccumulation (logKow) of NNIs on earthworms. A comprehensive effects three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed, using NNIs molecular structures and the comprehensive effect value as the independent and dependent variables, respectively. One of the representatives guadipyr (GUA) was selected as the template molecule for the molecular design and modification. A total of 63 NNIs alternatives were designed with a reduced comprehensive value higher than 10%, and as high as 42%. After screening, 15 NNIs alternatives were screened with decreased acute toxicity to earthworms, bioaccumulation effects and improved functional property. The calculated primary acute risk quotient of earthworms shows that the designed NNIs alternatives have lower earthworm risks (reduction of 70.48-99.99%). Results also found that the electronic, geometric and topological parameters of NNIs are the key descriptors that affect NNIs alternatives' toxicity. The number of hydrophobic interaction amino acid residues in NNIs molecules also contributes to the acute toxicity and the bioaccumulation of NNIs alternatives on earthworms. This study aims to design and screen functionally improved and environmentally friendly NNIs alternatives that have low risk to earthworms and provide theoretical methods and new ideas for the risk control and development of pesticides represented by NNIs.

A novel pharmacophore model on PAEs' estrogen and thyroid hormone activities using the TOPSIS and its application in molecule modification.

In the proposed model, the estrogen activity values and thyroid hormone activity values of PAEs molecules were normalized using the TOPSIS method by eliminating the dimension coefficients, and the comprehensive activity values of estrogen and thyroid hormone were obtained by analyzing the activity of each hormone and assigning the corresponding weight. The five pharmacophore models of hormone combined activity were constructed using the comprehensive activity values. Hypol 1 was the optimal pharmacophore model, showing good predictive power and significance. Then, the DBP, DNOP, and DMP molecules in environmental priority control pollutants were selected as the target molecules to perform common substitution reactions of hydrogen bond donor. Eleven PAEs derivative molecules with significantly reduced combined activity and single activity were screened. In analysis of the differences before and after modification of the docking parameters and amino acid residues before and after modification of PAEs and their derivatives, the reduced closeness between ligand and receptor leads to the decrease of thyroid hormones and estrogen activities. Moreover, the establishment of the models, not only shows that the PAEs hormone activity has certain linear relationships with the physical parameters of molecules but also shows that thyroid hormone activity and estrogen activity of PAEs is consistent with the hormone combined activity. The results confirmed the feasibility of the modified PAEs modification scheme with reduced combined activities of hormones, providing an important theoretical method for the construction of the pharmacophore model of combined activities of hormones and the study of PAEs derivative molecules.