An integrated screening strategy for novel AhR agonist candidate identification and toxicity confirmation in...

Organic contaminants showing aryl hydrocarbon receptor (AhR) agonist activity are commonly detected in areas disturbed by intense human activities and they can initiate a variety of biochemical, physiological, and toxicological effects. A new integrated screening strategy for AhR agonist candidate identification and toxicity confirmation was developed to characterize the AhR-active pollutants in sediments of the contaminated Daqing River basin (DRB) in North China. The specific objectives were to (i) determine the concentrations of known AhR agonists, (ii) identify the novel AhR agonist candidates from nontarget screening (NTS) with structure alerts, computational toxicology (CompTox) Dashboard bioassays, and in silico predictions, and (iii) evaluate contributions of AhR agonists to the overall potencies and characterize the distribution and source of these pollutants. Significant AhR-mediated potencies were observed in all sediment extracts by in vitro bioassays. Concentrations of polar target chemicals in sediment extracts were much lower than nonpolar target chemicals. A total of 19 known AhR agonists explained 11.3 % to 49.1 % of bioassay-derived AhR-mediated potencies and polychlorinated biphenyls (PCB) 126 and PCB169 were found to contribute significantly to the total effects. 21 compounds screened from NTS by AhR-related structure alerts and further confirmed toxicity by high-throughput bioassays and in silico predictions were selected as AhR agonist candidates. Most of them were substituted PAHs, biphenyls, quinones, substituted phenols and heterocyclic compounds, and they primarily originated from nearby manufacturing industries. Of these compounds, 1-methy-pyrene exhibited significant AhR-mediated potency. Follow up studies should focus on toxicological mechanism, source, and fate of these novel AhR agonists in water environment.