Perfluorooctane sulfonate (PFOS) interferes with Cyp1a activity and dysregulates the aryl hydrocarbon receptor pathway in larval zebrafish (Danio rerio).

Per- and poly- fluoroalkyl substances (PFAS) are ubiquitous, persistent toxicants. In the environment, PFAS co-occur with other compounds, including agonists of the aryl hydrocarbon receptor (AHR). In this study, in silico molecular docking, in vitro enzyme activity, and the in vivo zebrafish model were used to identify PFAS that may interact with the AHR pathway and assess impacts for developmental toxicity. Of the PFAS and proteins modeled, perfluorooctane sulfonate (PFOS) was predicted in silico by AutoDock Vina to have good affinity for CYP1A1 . This prediction was supported by enzyme inhibition assays in vitro, where PFOS inhibited human CYP1A1 (estimated IC50 of 35 μM). For in vivo testing, two PFAS were selected: PFOS and the related perfluorohexane sulfonate (PFHxS), which did not inhibit CYP1A1 activity at tested concentrations in vitro. Zebrafish embryos were exposed from 24 to 100 hours post-fertilization to mixtures of PFAS (16 μM) with and without the AHR agonist β-naphthoflavone (βNF; 3.67, 36.7, and 183.6 nM). Co-exposures of βNF and PFOS caused severe morphological deformities not observed with either compound alone, accompanied by reduced Cyp1a-like enzyme activity, and cyp1a gene expression. In contrast, PFHxS did not interfere with Cyp1a activity in vivo and did not cause developmental toxicity. This suggests developmental toxicity of mixtures containing PFOS may be underestimated, and identification of other PFAS that interact with the AHR pathway is warranted.