Assessment of Ah receptor transcriptional activity mediated by halogenated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) in human and mouse cell systems

Kari L. Organtini, Troy D. Hubbard, Gary H. Perdew, Franklin Lewis Dorman, Jr.

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3 Citations (Scopus)

Abstract

Polybrominated and mixed bromo/chloro dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) are emerging environmental contaminants of concern. Thus far, an understanding of the toxicological behavior of these chemical species and their impact upon human health is incomplete. Here we utilized human and mouse hepatocellular carcinoma cell lines to examine the ability of differentially halogenated PXDD/F congeners to induce aryl hydrocarbon receptor (AHR)-mediated transcriptional activity. Dose-response experiments in reporter cell lines identified varied potencies among differentially halogenated PXDD/F isomers by comparison of EC50 values relative to the prototypical AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Brominated PXDD/F species displayed reduced capacity to activate the mouse AHR, compared to TCDD. Only BrCl3 dibenzo-p-dioxin was found to have a greater relative potency than TCDD to induce human AHR transcriptional activity. Human cells required ∼10–29-fold higher ligand concentrations to induce analogous AHR activity, relative to mouse cells. Decreased sensitivity of the human AHR to brominated dibenzofuran congeners directly corresponded to the number of bromine functional groups. Mixtures of these compounds exhibited an additive effect on AHR activation. The data also support the inclusion of mixed halogenated dibenzo-p-dioxins and dibenzofurans into routine environmental screening procedures as well as more thorough toxicological characterization of PXDD/Fs.

Original languageEnglish (US)
Pages (from-to)1295-1302
Number of pages8
JournalJournal of Environmental Science and Health - Part A Toxic/Hazardous Substances and Environmental Engineering
Volume52
Issue number14
DOIs
StatePublished - Dec 6 2017

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Hydrocarbons
Cells
Bromine
Isomers
Functional groups
Screening
Chemical activation
Ligands
Health
Impurities
Experiments

All Science Journal Classification (ASJC) codes

  • Environmental Engineering

Cite this

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title = "Assessment of Ah receptor transcriptional activity mediated by halogenated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) in human and mouse cell systems",
abstract = "Polybrominated and mixed bromo/chloro dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) are emerging environmental contaminants of concern. Thus far, an understanding of the toxicological behavior of these chemical species and their impact upon human health is incomplete. Here we utilized human and mouse hepatocellular carcinoma cell lines to examine the ability of differentially halogenated PXDD/F congeners to induce aryl hydrocarbon receptor (AHR)-mediated transcriptional activity. Dose-response experiments in reporter cell lines identified varied potencies among differentially halogenated PXDD/F isomers by comparison of EC50 values relative to the prototypical AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Brominated PXDD/F species displayed reduced capacity to activate the mouse AHR, compared to TCDD. Only BrCl3 dibenzo-p-dioxin was found to have a greater relative potency than TCDD to induce human AHR transcriptional activity. Human cells required ∼10–29-fold higher ligand concentrations to induce analogous AHR activity, relative to mouse cells. Decreased sensitivity of the human AHR to brominated dibenzofuran congeners directly corresponded to the number of bromine functional groups. Mixtures of these compounds exhibited an additive effect on AHR activation. The data also support the inclusion of mixed halogenated dibenzo-p-dioxins and dibenzofurans into routine environmental screening procedures as well as more thorough toxicological characterization of PXDD/Fs.",
author = "Organtini, {Kari L.} and Hubbard, {Troy D.} and Perdew, {Gary H.} and {Dorman, Jr.}, {Franklin Lewis}",
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T1 - Assessment of Ah receptor transcriptional activity mediated by halogenated dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) in human and mouse cell systems

AU - Organtini, Kari L.

AU - Hubbard, Troy D.

AU - Perdew, Gary H.

AU - Dorman, Jr., Franklin Lewis

PY - 2017/12/6

Y1 - 2017/12/6

N2 - Polybrominated and mixed bromo/chloro dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) are emerging environmental contaminants of concern. Thus far, an understanding of the toxicological behavior of these chemical species and their impact upon human health is incomplete. Here we utilized human and mouse hepatocellular carcinoma cell lines to examine the ability of differentially halogenated PXDD/F congeners to induce aryl hydrocarbon receptor (AHR)-mediated transcriptional activity. Dose-response experiments in reporter cell lines identified varied potencies among differentially halogenated PXDD/F isomers by comparison of EC50 values relative to the prototypical AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Brominated PXDD/F species displayed reduced capacity to activate the mouse AHR, compared to TCDD. Only BrCl3 dibenzo-p-dioxin was found to have a greater relative potency than TCDD to induce human AHR transcriptional activity. Human cells required ∼10–29-fold higher ligand concentrations to induce analogous AHR activity, relative to mouse cells. Decreased sensitivity of the human AHR to brominated dibenzofuran congeners directly corresponded to the number of bromine functional groups. Mixtures of these compounds exhibited an additive effect on AHR activation. The data also support the inclusion of mixed halogenated dibenzo-p-dioxins and dibenzofurans into routine environmental screening procedures as well as more thorough toxicological characterization of PXDD/Fs.

AB - Polybrominated and mixed bromo/chloro dibenzo-p-dioxins and dibenzofurans (PXDD/Fs) are emerging environmental contaminants of concern. Thus far, an understanding of the toxicological behavior of these chemical species and their impact upon human health is incomplete. Here we utilized human and mouse hepatocellular carcinoma cell lines to examine the ability of differentially halogenated PXDD/F congeners to induce aryl hydrocarbon receptor (AHR)-mediated transcriptional activity. Dose-response experiments in reporter cell lines identified varied potencies among differentially halogenated PXDD/F isomers by comparison of EC50 values relative to the prototypical AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Brominated PXDD/F species displayed reduced capacity to activate the mouse AHR, compared to TCDD. Only BrCl3 dibenzo-p-dioxin was found to have a greater relative potency than TCDD to induce human AHR transcriptional activity. Human cells required ∼10–29-fold higher ligand concentrations to induce analogous AHR activity, relative to mouse cells. Decreased sensitivity of the human AHR to brominated dibenzofuran congeners directly corresponded to the number of bromine functional groups. Mixtures of these compounds exhibited an additive effect on AHR activation. The data also support the inclusion of mixed halogenated dibenzo-p-dioxins and dibenzofurans into routine environmental screening procedures as well as more thorough toxicological characterization of PXDD/Fs.

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