Aryl Hydrocarbon Receptor Activation Mediates Acute Lethality and Developmental Toxicity of Polychlorinated Diphenyl Ethers in Vertebrates: Mechanistic Insights and Implications for Toxicity Equivalency Factor Frameworks

The toxicological mechanism(s) of polychlorinated diphenyl ethers (PCDEs) in vertebrates remains unresolved. To test the hypothesis that PCDE-induced acute lethality and developmental toxicity are mediated by aryl hydrocarbon receptor (AHR) activation, wild-type, Tg(cyp1a:gfp) transgenic, and Ahr2-null zebrafish were exposed to 11 PCDE congeners commonly detected in the environment. Compared to wild-type zebrafish, where Ahr2 activation was confirmed by robust GFP induction in Tg(cyp1a:gfp) larvae, Ahr2-null larvae exhibited significantly reduced mortality and malformation percentages (e.g., 68.7-78.8% and 48.3-97.2% lower for three highly potent congeners CDE 15, 37, and 118, respectively), demonstrating Ahr2 as the primary mediator of PCDE-induced toxicity. Furthermore, complementary in vitro species-specific luciferase reporter gene (LRG) assays revealed significant dioxin-like activities of PCDEs in zebrafish, avian (chicken, pheasant, quail), and rat models, with interspecies potency variations of up to 27,000-fold. Notably, some PCDEs exhibited relative potencies comparable to or exceeding those of known dioxin-like compounds, including HO-/MeO-polybrominated diphenyl ethers, polychlorinated diphenyl sulfides, and several highly halogenated dibenzo-p-dioxins and dibenzofurans. Overall, these findings indicate that AHR activation serves as the primary molecular mechanism underlying the toxicity of PCDEs in vertebrates and provide critical data for ecological risk assessment. Given their structural similarity to dioxins and significant bioaccumulation potential, PCDEs should be considered for inclusion in global toxicity equivalency factor frameworks.