AhR Agonist Activity Confirmation of Polyhalogenated Carbazoles (PHCZs) Using an Integration of in Vitro, in Vivo, and in Silico Models

Polyhalogenated carbazoles (PHCZs) are a kind of rising environmental pollutant that has been reported to pose high risk to human beings and the natural environment. PHCZs are of a similar molecular structure with of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and exhibited some dioxin-like toxicity. Dioxin-like compounds (DLCs) arc banned by the Stockholm Convention due to their potential adverse impacts to the environment and public health. However, a few efforts have been made toward the regulation of PHCZs. Herein, we initiated multimodels to systematically determine and validate the dioxin-like effects of PHCZs on a large scale. Transgenic zebrafish line-Tg(cyp1a-12DRE:EGFP) and stably transfected HepG2 cell line with luciferase reporter plasmids were used to screen and evaluate the aryl hydrocarbon receptor (AhR) agonist effects of the target PHCZs, which were then verified by application of molecular docking and expression levels of AhR downstream genes. Results of the two bioassays showed that most of the tested PHCZs could pose dioxin-like AhR agonist effects, change the expression levels of AhR downstream genes, and interact with AhR in accordance with TCDD. In summary, data presented here can help to guide the safe use and regulation of PHCZs.