Induction of AhR transactivation by PBDD/Fs and PCDD/Fs using a novel human-relevant, high-throughput DRhuman CALUX reporter gene assay

Clémence Budin*, Harrie Besselink, Barbara M.A. van Vugt-Lussenburg, Hai Yen Man, Bart van der Burg, Abraham Brouwer

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Polychlorinated dioxins and dibenzofurans (PCDD/Fs) are highly toxic contaminants that are strictly regulated and monitored in the environment and food to reduce human exposure. Recently, the increasing occurrence of polybrominated dioxins and dibenzofurans (PBDD/Fs) in the environment is raising concerns about the impact on human health by the combined exposure to chlorinated and brominated analogues of dioxins. Toxicological properties of PBDD/Fs relative to PCDD/Fs have not been firmly established, and brominated dioxins are not included in routine monitoring programs. In this study, we set out to determine human-relevant congener-specific potency values for a range of brominated and chlorinated dioxin congeners, based on their aryl hydrocarbon receptor (AhR)-mediated mode of toxic action. Transactivation of the AhR was measured using dioxin-responsive (DR) CALUX reporter gene assays. Because of known species-differences in dioxin-mediated toxicity, we developed and used a HepG2 human liver cell-based DR human CALUX assay that is a variant of the rodent-based DR CALUX. The assay was found to be highly inducible and stable, with low variations between independent measurements. Using both DR CALUX assays in an automated high-throughput mode we found that overall PBDD/Fs were as potent as PCDD/Fs in inducing AhR transactivation, but congener-specific differences were observed. We also observed species-specific differences in sensitivity and potency when comparing DR human REP values to those obtained in the rat-based DR CALUX. Finally, we observed significant differences between WHO-TEF values and DR human REP values, suggesting that actual WHO-TEF values may underestimate the hazards associated with exposure of humans to dioxins.

Original languageEnglish
Article number128086
Pages (from-to)1-9
Number of pages9
JournalChemosphere
Volume263
Early online date23 Aug 2020
DOIs
Publication statusPublished - Jan 2021

Keywords

  • Bioassays
  • Dioxins
  • DR CALUX
  • High-throughput screening
  • Polybrominated dibenzo-p-dioxin and dibenzofuran (PBDD/Fs)
  • Polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/Fs)

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