Comparison of transcriptomic points of departure with apical endpoints in developing zebrafish exposed to PFOS, PFOA, or PFHxS

Zebrafish are widely leveraged for investigating per- and polyfluoroalkyl substance (PFAS) toxicity; however, there exists a data gap for employing zebrafish transcriptomic data for PFAS quantitative risk assessment. The present study exposed developing zebrafish at different start times and durations to 0 to 100 µM of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexanesulfonic acid (PFHxS) to examine chemical-specific effects on transcriptomics-based point of departure estimates (tPODs). Study goals were to investigate if the tPODs were robust to differences in exposure start and duration, were protective of zebrafish apical outcomes, and were similar to recently published PFAS tPODs in other model organisms. Zebrafish tPODs were within 1.5 orders of magnitude across the 3 chemicals, exposure durations, and start times, except for the shortest and earliest exposure (6 to 24 h post fertilization) for PFOS/PFOA. Although corresponding apical endpoints were influenced by exposure scenario, tPODs were generally lower, and thus protective of zebrafish mortality and sublethal endpoints. The relationship between our tPODs and literature zebrafish toxicity effects was chemical-specific; only the PFOA tPODs were protective of all apical effects together, and PFOS/PFHxS tPODs were generally within the interquartile range of the effects concentrations. The zebrafish PFAS tPODs were also similar to previously published fathead minnow tPODs, whereas only the PFOS zebrafish tPODs were within one order of magnitude of the Daphnia magna PFOS tPOD. Our study emphasizes that the high-throughput-compatible, in vivo developmental zebrafish platform is a feasible tool for detecting dose-dependent gene expression responses that can be leveraged for higher-tier assessments.