Review of the zebrafish as a model to investigate per- and polyfluoroalkyl substance toxicity.

This article focuses on the use of the zebrafish model to assess the toxicokinetics, toxicity, adverse health outcomes, and potential modes of action of per- and polyfluoroalkyl substances (PFAS), a large class of persistent anthropogenic chemicals. Zebrafish enable rapid, high-throughput in vivo testing across diverse PFAS structures, facilitating comparisons and prioritization of compounds for further study. Findings indicate that PFAS toxicity and bioconcentration generally increase with longer fluorinated carbon chain length and the presence of sulfonamide or sulfonic acid functional groups, with effects observed on lipid metabolism, oxidative stress, nervous, cardiac, endocrine, and immune systems. Transcriptomic and multi-omics analyses have identified key disrupted pathways and potential mediators such as Nrf2a, PPAR, and AHR, though further mechanistic research and expanded testing of structurally diverse PFAS are needed. The review highlights the importance of standardized testing conditions, analytical validation, and consideration of mixture effects to improve hazard assessment and regulatory decision-making.