QSTR Models in Dioxins and Dioxin-like Compounds Provide Insights into Gene Expression Dysregulation.

Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) are a group of organic chemicals containing three-ring structures that can be substituted with one to eight chlorine atoms, leading to 75 dioxin and 135 furan congeners. As endocrine-disrupting chemicals (EDCs), they can alter physiological processes causing a number of disorders. In this study, quantitative structure-toxicity relationship (QSTR) studies were used to determine the correlations between the PCDD/Fs' molecular structures and various toxicity endpoints. Strong QSTR models, with the coefficients of determination (r2) values greater than 0.95 and ANOVA p-values less than 0.0001 were established between molecular descriptors and the endpoints of bioconcentration, fathead minnow LC50, and Daphnia magna LC50. The ability of PCDD/Fs to bind to several nuclear receptors was investigated via molecular docking studies. The results show comparable, and in some instances better, binding affinities of PCDD/Fs toward the receptors relative to their natural agonistic and antagonistic ligands, signifying possible interference with the receptors' natural biological activities. These studies were accompanied by the molecular dynamics simulations of the top-binding PCDD/Fs to show changes in the receptor-ligand complexes during binding and provide insights into these compounds' ability to interfere with transcription and thereby modify gene expression. This introspection of PCDD/Fs at the molecular level provides a deeper understanding of these compounds' toxicity and opens avenues for future studies.

Theoretical Studies on the Quantitative Structure-Toxicity Relationship of Polychlorinated Biphenyl Congeners Reveal High Affinity Binding to Multiple Human Nuclear Receptors.

Polychlorinated biphenyls (PCBs) are organic chemicals consisting of a biphenyl structure substituted with one to ten chlorine atoms, with 209 congeners depending on the number and position of the chlorine atoms. PCBs are widely known to be endocrine-disrupting chemicals (EDCs) and have been found to be involved in several diseases/disorders. This study takes various molecular descriptors of these PCBs (e.g., molecular weight) and toxicity endpoints as molecular activities, investigating the possibility of correlations via the quantitative structure-toxicity relationship (QSTR). This study then focuses on molecular docking and dynamics to investigate the docking behavior of the strongest-binding PCBs to nuclear receptors and compares these to the docking behavior of their natural ligands. Nuclear receptors are a family of transcription factors activated by steroid hormones, and they have been investigated to consider the impact of PCBs on humans in this context. It has been observed that the docking affinity of PCBs is comparable to that of the natural ligands, but they are inferior in terms of stability and interacting forces, as shown by the RMSD and total energy values. However, it is noted that most nuclear receptors respond to PCBs similarly to how they respond to their natural ligands-as shown in the RMSF plots-the most similar of which are seen in the ER, THR-ß, and RAR-α. However, this study is performed purely in silico and will need experimental verification for validation.