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

ABSTRACT: Polychlorinated dibenzofurans (PCDFs) are known to cause endocrine disruption in humans and wildlife but the mechanisms underlying this disruption have not been adequately investigated. In this paper, the susceptibility of the endocrine system to disruption by PCDF congeners via nuclear receptor binding was studied using molecular docking simulation. Findings revealed that some PCDF congeners exhibit high probabilities of binding to androgen receptor in its agonistic and antagonistic conformations. In depth molecular docking analysis of the receptor-ligand complexes formed by PCDFs with androgen receptor in its agonistic and antagonistic conformations showed that, these complexes were stabilized by electrostatic, van der Waals, pi-effect and hydrophobic interactions. It was also observed that PCDF molecules mimic the modes of interaction observed in androgen-testosterone and androgen-bicalutamide complexes, utilizing between 65 and 83% of the amino acid residues used by the co-crystallized ligands for binding. This computational study suggests that some PCDF congeners may act as agonists and antagonists of androgen receptor in humans and wildlife via inapproprate binding to the receptor.

SUBMITTER: Akinola LK

PROVIDER: S-EPMC8515090 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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<i>In silico</i> prediction of nuclear receptor binding to polychlorinated dibenzofurans and its implication on endocrine disruption in humans and wildlife.

Akinola Lukman K LK Uzairu Adamu A Shallangwa Gideon A GA Abechi Stephen E SE

Current research in toxicology 20210930

Polychlorinated dibenzofurans (PCDFs) are known to cause endocrine disruption in humans and wildlife but the mechanisms underlying this disruption have not been adequately investigated. In this paper, the susceptibility of the endocrine system to disruption by PCDF congeners via nuclear receptor binding was studied using molecular docking simulation. Findings revealed that some PCDF congeners exhibit high probabilities of binding to androgen receptor in its agonistic and antagonistic conformatio ...[more]

PMID: 34693345

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Project description:Proximity to facilities emitting polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F) has been associated with increased risk of non-Hodgkin lymphoma (NHL). There is limited information about whether proximity to industrial sources leads to indoor PCDD/F contamination of homes. We measured carpet dust concentrations (pg/g) of 17 toxic PCDD/F congeners and calculated their toxic equivalence (TEQ) in 100 homes in a population-based case-control study of NHL in Detroit, Los Angeles, Seattle, and Iowa (1998-2000). We took global positioning system readings at residences and obtained coordinates and PCDD/F emissions (ng TEQ/yr) from an Environmental Protection Agency database for 6 facility types: coal-fired electricity generating plants, cement kilns burning non-hazardous waste, hazardous waste incinerators, medical waste incinerators, municipal solid waste incinerators, and sewage sludge incinerators. For each residence, we computed an inverse distance-squared weighted average emission index (AEI [pg TEQ/km2/yr]) for all facilities within 5km from 1983 to 2000. We also computed AEIs for each of the 6 facility types. We evaluated relationships between PCDD/F dust concentrations and the all-facility AEI or categories of facility-type AEIs using multivariable linear regression, adjusting for study center, demographics, and home characteristics. A doubling of the all-facility AEI was associated with a 4-8% increase in PCDD/F dust concentrations of 7 of 17 PCDD/F congeners and the TEQ (p-value<0.1). We also observed positive associations between PCDD/F dust concentrations and facility-type AEIs (highest vs. lowest exposure category) for municipal solid waste incinerators (9 PCDD/F, TEQ), and medical waste incinerators (7 PCDD/F, TEQ) (p<0.1). Our results from diverse geographical areas suggest that industrial PCDD/F emission sources contribute to residential PCDD/F dust concentrations. Our emissions index could be improved by incorporating local meteorological data and terrain characteristics. Future research is needed to better understand the links between nearby emission sources, human exposure pathways, and health risks.

Dataset Information

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

Publications

<i>In silico</i> prediction of nuclear receptor binding to polychlorinated dibenzofurans and its implication on endocrine disruption in humans and wildlife.

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