Derivation of Transcriptomics‐Based Points of Departure for 20 Per‐ or Polyfluoroalkyl Substances Using a Larval Fathead Minnow (Pimephales promelas) Reduced Transcriptome Assay

Abstract Traditional toxicity testing has been unable to keep pace with the introduction of new chemicals into commerce. Consequently, there are limited or no toxicity data for many chemicals to which fish and wildlife may be exposed. Per‐ and polyfluoroalkyl substances (PFAS) are emblematic of this issue in that ecological hazards of most PFAS remain uncharacterized. The present study employed a high‐throughput assay to identify the concentration at which 20 PFAS, with diverse properties, elicited a concerted gene expression response (termed a transcriptomics‐based point of departure [tPOD]) in larval fathead minnows ( Pimephales promelas ; 5–6 days postfertilization) exposed for 24 h. Based on a reduced transcriptome approach that measured whole‐body expression of 1832 genes, the median tPOD for the 20 PFAS tested was 10 µM. Longer‐chain carboxylic acids (12–13 C–F); an eight‐C–F dialcohol, N ‐alkyl sulfonamide; and telomer sulfonic acid were among the most potent PFAS, eliciting gene expression responses at concentrations <1 µM. With a few exceptions, larval fathead minnow tPODs were concordant with those based on whole‐transcriptome response in human cell lines. However, larval fathead minnow tPODs were often greater than those for Daphnia magna exposed to the same PFAS. The tPODs overlapped concentrations at which other sublethal effects have been reported in fish (available for 10 PFAS). Nonetheless, fathead minnow tPODs were orders of magnitude higher than aqueous PFAS concentrations detected in tributaries of the North American Great Lakes, suggesting a substantial margin of safety. Overall, results broadly support the use of a fathead minnow larval transcriptomics assay to derive screening‐level potency estimates for use in ecological risk‐based prioritization. Environ Toxicol Chem 2024;00:1–16. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.