Identification of Novel Polar Aryl Hydrocarbon Receptor Agonists Accumulated in Liver of Black-Tailed Gulls in Korea Using Advanced Effect-Directed Analysis

Although bioaccumulation of persistent organic pollutants in seabirds has been examined, few studies have been conducted to identify previously unidentified substances. Here, aryl hydrocarbon receptor (AhR) agonists were identified in livers of black-tailed gulls from South Korea using effect-directed analysis combined with full-scan screening analysis. Significant AhR-mediated potencies were observed in the polar fractions of liver extracts using H4IIE-luc bioassay. Eight known polar AhR agonists accounted for 11-20% of the total AhR-mediated potencies in the polar fractions; hydrocortisone and rutaecarpine were the major contributors. Twenty-two AhR agonist candidates in the polar fractions were identified using liquid chromatography-quadrupole timeof-flight mass spectrometry during a six-step selection process. Of these, [10]-gingerol, angelicin, corticosterone, eupatilin, etofenpmx, oxadixyl, and tretinoin were identified as novel AhR agonists. The contribution to potencies increased with inclusion of novel AhR agonists (27-52%); corticostemne and [10]-gingerol contributed significantly. Quantitative structure-activity relationship suggested that the novel AhR agonists have other potential toxic effects, including carcinogenicity and mutagenicity. Polar AhR agonists have been used for pharmaceuticals and pesticides. Some novel AhR agonists have log K-OW > 2 and log K-OA >= 6, which indicates that these compounds can be biomagnified in air-breathing organisms, such as seabirds.