Theoretical study on endocrine disrupting effects of polychlorinated dibenzo‐p‐dioxins using molecular docking simulation

Abstract

Polychlorinated dibenzo-p-dioxins (PCDDs) are hypothesized to exert their toxic effects in wildlife and humans via endocrine disruption. However, very scanty information is available on the underlying molecular interactions that trigger this disruption. In this study, molecular docking simulation was used to predict the susceptibility of 12 nuclear receptors to disruption via PCDD bindings. Findings revealed that androgen (AR and AR an), estrogen (ER α and ER β), glucocorticoid (GR) and thyroid hormone (TR α and TR β) receptors are the most probable protein targets that bind to PCDDs. Further molecular docking analyses showed that PCDD molecules mimic the modes of interaction observed for the co-crystallized ligands of the affected receptors, resulting in the formation of ligand-receptor complexes that were stabilized through electrostatic, van der Waals, pi-effect and hydrophobic interactions with 18, 17, 17, 16, 18, eight and four amino acid residues in the active sites of AR, AR an, ER α, ER β, GR, TR α and TR β respectively. The commonalities of these interacting amino acid residues with those utilized by dihydrotestosterone in AR, bicalutamide in AR an, 17β-estradiol in ER α, 17β-estradiol in ER β, cortisol in GR, thyromimetic GC-1 in TR α and thyromimetic GC-1 in TR β are 86%, 74%, 94%, 80%, 82%, 50% and 43% respectively. The results obtained in this study provide supporting evidence that PCDD molecules may interfere with the endocrine system via binding interactions with some vital amino acid residues in the binding pockets of AR, ERs, GRs and TRs.

Impact of Endocrine Disruptors upon Non-Genetic Inheritance

“…This results in the presence of a dioxin level higher than the tolerable weekly intake in the environment [ 47 ]. Dioxin inhibits estrogen-receptor-mediated gene transcription and modulates the expression or interact directly with steroid receptors [ 48 ]. TCDD promotes epigenetic transgenerational inheritance of disease and DNA methylation epimutations in sperm.…”

“…PCBs can interact with steroid receptors or modulate their expression. Based on the in silico simulation of molecule interactions, it was concluded that PCBs were able to interfere with the reproductive process [ 48 ]. PCBs decreased the force and amplitude of oviductal motility and some of them also stimulated the synthesis of leukemia inhibitory factor (LIF).…”

In silico prediction of nuclear receptor binding to polychlorinated dibenzofurans and its implication on endocrine disruption in humans and wildlife

“…It should be realized that the predictions made by endocrine disruptome are not equally reliable for the different protein targets available for testing in the software, as some targets suffer from bias ( Kolšek et al, 2014 ). Endocrine disruptome has been successfully employed for the prediction of endocrine-disrupting potentials of some chemical substances ( Akinola et al, 2021 , Akinola et al, 2021 , Kenda and Dolenc, 2020 , Plošnik et al, 2015 , Usman and Ahmad, 2019 , Wang et al, 2020 ).…”

Fluid dynamic design for mitigating undesired cell effects and its application to testis cell response testing to endocrine disruptors

“…Furthermore, we demonstrated the application of the gradient chip for endocrine disruptors (EDs) test on testis cells cultured in our system. EDs accumulate in the human body and interfere with normal homeostatic control, reproduction, and developmental processes [ 22 ]. Especially, it is known that one of the EDs that is frequently used in the manufacture of various plastics, bisphenol-A (BPA), is easily internalized in the body.…”