Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway

A. K. Peters, S. Nijmeijer, K. Gradin, M. Backlund, Å Bergman, L. Poellinger, M. S. Denison, M. Van den Berg

Research output: Contribution to journalArticle

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Abstract

Polybrominated diphenyl ethers (PBDEs) are brominated flame retardants that have been in use as additives in various consumer products. Structural similarities of PBDEs with other polyhalogenated aromatic hydrocarbons that show affinity for the aryl hydrocarbon receptor (AhR), such as some polychlorinated biphenyls, raised concerns about their possible dioxin-like properties. We studied the ability of environmentally relevant PBDEs (BDE-47, -99, -100, -153, -154, and -183) and the "planar" congener BDE-77 to bind and/or activate the AhR in stably transfected rodent hepatoma cell lines with an AhR-responsive enhanced green fluorescent protein (AhR-EGFP) reporter gene (H1G1.1c3 mouse and H4G1.1c2 rat hepatoma). 7-Ethoxyresorufin-O-deethylation (EROD) was used as a marker for CYP1A1 activity. Dose- and bromination-specific inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced responses was measured by their ability to inhibit the induction of AhR-EGFP expression and EROD activity. Individual exposure to these PBDEs did not result in any increase in induction of AhR-EGFP or CYP1A1 activity. The lower brominated PBDEs showed the strongest inhibitory effect on TCDD-induced activities in both cell lines. While the highest brominated PBDE tested, BDE-183, inhibited EROD activity, it did not affect the induction of AhR-EGFP expression. Similar findings were observed after exposing stably transfected human hepatoma (xenobiotic response element [XRE]-HepG2) cells to these PBDEs, resulting in a small but statically significant agonistic effect on XRE-driven luciferase activity. Co-exposure with TCDD resulted again in antagonistic effects, confirming that the inhibitory effect of these PBDEs on TCDD-induced responses was not only due to direct interaction at receptor level but also at DNA-binding level. This antagonism was confirmed for BDE-99 in HepG2 cells transiently transfected with a Gal4-AhR construct and the corresponding Gal4-Luc reporter gene. In addition, a chromatin immunoprecipitation assay further confirmed that BDE-99 could bind to the AhR and activate the AhR nuclear translocation and dioxin responsive element (DRE) binding in the context of the CYP1A1 promoter. However, the transactivation function of the BDE-99-activated AhR seems to be very weak. These combined results suggest that PBDEs do bind but not activate the AhR-AhR nuclear translocator protein-XRE complex.

Original languageEnglish (US)
Pages (from-to)133-142
Number of pages10
JournalToxicological Sciences
Volume92
Issue number1
DOIs
StatePublished - Jul 2006

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Halogenated Diphenyl Ethers
Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A1
Response Elements
Xenobiotics
Hepatocellular Carcinoma
Dioxins
Hep G2 Cells
Reporter Genes
Aryl Hydrocarbon Receptor Nuclear Translocator
Genes
Cells
Flame Retardants
Aromatic Hydrocarbons
Cell Line
Consumer products
Chromatin Immunoprecipitation
Halogenation
Polychlorinated Biphenyls
Nuclear Proteins

Keywords

  • AhR-EGFP
  • Aryl hydrocarbon receptor
  • EROD
  • PBDE
  • XRE

ASJC Scopus subject areas

  • Toxicology

Cite this

Peters, A. K., Nijmeijer, S., Gradin, K., Backlund, M., Bergman, Å., Poellinger, L., ... Van den Berg, M. (2006). Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. Toxicological Sciences, 92(1), 133-142. https://doi.org/10.1093/toxsci/kfj186

Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. / Peters, A. K.; Nijmeijer, S.; Gradin, K.; Backlund, M.; Bergman, Å; Poellinger, L.; Denison, M. S.; Van den Berg, M.

In: Toxicological Sciences, Vol. 92, No. 1, 07.2006, p. 133-142.

Research output: Contribution to journalArticle

Peters, AK, Nijmeijer, S, Gradin, K, Backlund, M, Bergman, Å, Poellinger, L, Denison, MS & Van den Berg, M 2006, 'Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway', Toxicological Sciences, vol. 92, no. 1, pp. 133-142. https://doi.org/10.1093/toxsci/kfj186
Peters AK, Nijmeijer S, Gradin K, Backlund M, Bergman Å, Poellinger L et al. Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. Toxicological Sciences. 2006 Jul;92(1):133-142. https://doi.org/10.1093/toxsci/kfj186
Peters, A. K. ; Nijmeijer, S. ; Gradin, K. ; Backlund, M. ; Bergman, Å ; Poellinger, L. ; Denison, M. S. ; Van den Berg, M. / Interactions of polybrominated diphenyl ethers with the aryl hydrocarbon receptor pathway. In: Toxicological Sciences. 2006 ; Vol. 92, No. 1. pp. 133-142.
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