Assessment of Risks of Dioxins for Aryl Hydrocarbon Receptor-Mediated Effects in Polar Bear (<i>Ursus maritimus</i>) by in Vitro and in Silico Approaches

Hwang, Ji-Hee; Evans, Thomas J.; Iwata, Hisato; Kim, Eun Young

doi:10.1021/acs.est.9b05941

Cited by 10 publications

(6 citation statements)

References 61 publications

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“…This may be because the AA residues conserved among birds may interact with species-specific AAs, thereby inducing species-specific interactions between AHR1 and dioxin-like ligands. This is consistent with previous findings in mammals, that is, AAs conserved among mammals may participate in the backbone interactions with polar bear AHR (pbAHR)-specific AAs, thereby leading to species-specific responses to ligands in pbAHR . It is worth noting that the two AA residues 324 and 380 are located in the regions discovered by the ML algorithm combined with MD simulations.…”

Section: Resultssupporting

confidence: 91%

Using In Vitro and Machine Learning Approaches to Determine Species-Specific Dioxin-like Potency and Congener-Specific Relative Sensitivity among Birds for Brominated Dioxin Analogues

Zhang

et al. 2021

Environ. Sci. Technol.

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There is a paucity of experimental data regarding dioxin-like toxicity of polybrominated dibenzo-p-dioxins/ dibenzofurans (PBDD/Fs) and non-ortho polybrominated biphenyls (PBBs). In this study, avian aryl hydrocarbon receptor 1 (AHR1)-luciferase reporter gene assays were used to determine their species-specific dioxin-like potencies (DLPs) and congenerspecific interspecies relative sensitivities in birds. The results suggested that DLPs of the brominated congeners for chicken-like (Ile324_Ser380) species did not always follow World Health Organization toxicity equivalency factors of their chlorinated analogues. For ring-necked pheasant-like (Ile324_Ala380) and Japanese quail-like (Val324_Ala380) species, the difference in DLP for several congeners was 1 or even 2 orders of magnitude. Moreover, molecular docking and molecular dynamics simulation were performed to explore the interactions between the brominated congeners and AHR1-ligand-binding domain (LBD). The molecular mechanics energy (E MM ) between each congener and each individual amino acid (AA) residue in AHR1−LBD was calculated. These E MM values could finely characterize the final conformation of species-specific AHR1−LBD for each brominated congener. Based on this, mechanism-driven generalized linear models were successfully built using machine learning algorithms and the spline approximation method, and these models could qualitatively predict the complex relationships between AHR1 conformations and DLPs or avian interspecies relative sensitivity to brominated dioxin-like compounds (DLCs). In addition, several AAs conserved among birds were found to potentially interact with species-specific AAs, thereby inducing species-specific interactions between AHR1 and brominated DLCs. The present study provides a novel strategy to facilitate the development of mechanism-driven computational prediction models for supporting safety assessment of DLCs, as well as a basis for the ecotoxicological risk assessment of brominated congeners in birds.

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Section: Resultssupporting

confidence: 91%

Using In Vitro and Machine Learning Approaches to Determine Species-Specific Dioxin-like Potency and Congener-Specific Relative Sensitivity among Birds for Brominated Dioxin Analogues

Zhang

et al. 2021

Environ. Sci. Technol.

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“…In brief, the structures of the ligand binding domains (LBD) of PXR and CAR were modeled based on the crystal structure from the RCSB Protein Data Bank (1XVP for CAR, and 3CTB for PXR) by using a Swiss-model server. As there is no proper crystal structure of human AhR in the database, the LBD of AhR was analogously modeled according to the template of HIF-2α (PDB: 3H7W), as validated in a recent report . The models of BPs and NR agonists were built by using Avogadro .…”

Section: Methodsmentioning

confidence: 99%

“…As there is no proper crystal structure of human AhR in the database, the LBD of AhR was analogously modeled according to the template of HIF-2α (PDB: 3H7W), as validated in a recent report. 42 The models of BPs and NR agonists were built by using Avogadro. 43 Then, molecular docking was performed by using AutoDock suits.…”

Section: ■ Introductionmentioning

confidence: 99%

Influence of Bisphenol Compounds at Nanomolar Concentrations on Chromosome Damage Induced by Metabolically Activated Carcinogens in HepG2 Cells

Song

et al. 2021

Environ. Sci. Technol.

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Bisphenol (BP) compounds are endocrine-disrupting organic pollutants. BPs may increase the messenger RNA (mRNA) transcripts of nuclear receptors (NRs) regulating the expression of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes. Their impact on the genotoxicity of metabolically activated carcinogens, however, remains unknown. In this study, effects of the bisphenols A, F, S, and AF on the expression of the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor, and individual xenobiotic-metabolizing CYP enzymes in a human hepatoma (HepG2) cell line were investigated, along with in silico binding studies of BPs to each receptor. The results indicated that each BP at 1 to 100 nM concentrations increased the mRNA transcripts and protein levels of AhR, PXR, CYP1A1, 1A2, 1B1, 2E1, and 3A4. The predicted affinities of the BPs for binding AhR were comparable to those of potent agonists. Pretreatment of HepG2 cells with each BP potentiated the induction of micronuclei by benzo[a]pyrene, aflatoxin B1, benzene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; this effect was abolished/reduced by inhibitors of NRs and/or CYPs. Our study suggests that BPs at human exposure levels may aggravate chromosome damage by several impactful carcinogens in human cells by inducing relevant CYP enzymes, mostly via NR modulation.

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“…As hypothesized by Landers and Bunce (1991), the sequence of events associated with AhR‐mediated toxicities of these toxicants involve: (i) entry of the toxicant molecule into the cell, (ii) binding of the toxicant molecule to AhR, (iii) binding of the receptor‐ligand complex to DNA recognition sites, (iv) expression of specific genes and the translation of their protein products, and (v) mode of action of the expressed proteins. Numerous empirical studies, linking the induction of PCDD toxicities to its binding with AhR abound in the literature (Hwang, Kannan, Evans, Iwata, & Kim, 2020; Thuruthippallil, Kim, Ishibashi, & Iwata, 2012; Thuruthippallil, Kubota, Kim, & Iwata, 2012). To the best of our knowledge, no in vivo or in vitro study that reports direct binding of PCDD molecules to AR, ERs, GRs and TRs is currently available in the literature.…”

Section: Discussionmentioning

confidence: 99%

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

Akinola

Uzairu

Shallangwa

et al. 2020

J of Applied Toxicology

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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.

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Assessment of Risks of Dioxins for Aryl Hydrocarbon Receptor-Mediated Effects in Polar Bear (Ursus maritimus) by in Vitro and in Silico Approaches

Cited by 10 publications

References 61 publications

Using In Vitro and Machine Learning Approaches to Determine Species-Specific Dioxin-like Potency and Congener-Specific Relative Sensitivity among Birds for Brominated Dioxin Analogues

Using In Vitro and Machine Learning Approaches to Determine Species-Specific Dioxin-like Potency and Congener-Specific Relative Sensitivity among Birds for Brominated Dioxin Analogues

Influence of Bisphenol Compounds at Nanomolar Concentrations on Chromosome Damage Induced by Metabolically Activated Carcinogens in HepG2 Cells

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

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