Induction of AhR transactivation by PBDD/Fs and PCDD/Fs using a novel human-relevant, high-throughput DRhuman CALUX reporter gene assay. (January 2021)

• Record Type: Journal Article
• Authors: Budin, Clémence; Besselink, Harrie; van Vugt-Lussenburg, Barbara M.A.; Man, Hai-Yen; van der Burg, Bart; Brouwer, Abraham
• Is Part Of: Chemosphere. Volume 263(2021)
• Publication Date: 2021-01
• Subjects: Dioxins -- Polybrominated dibenzo-p-dioxin and dibenzofuran (PBDD/Fs) -- Polychlorinated dibenzo-p-dioxin and dibenzofuran (PCDD/Fs) -- DR CALUX -- Bioassays -- High-throughput screening; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2020.128086
• Languages: English
• ISSNs: 0045-6535

Abstract

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. Highlights: The DRhuman CALUX is a highly inducible and stable AhR-mediated reporter gene assay. We determined DR CALUX and DRhuman CALUX REP values for PCDD/Fs and PBDD/Fs. Like PCDD/Fs, PBDD/Fs are potent activators of the human AhR. We observed species-specific differences between DR and DRhuman CALUX REPs. We observed significant differences between DRhuman REP values and WHO-TEF.