Per- and polyfluoroalkyl substances (PFAS) are a major focus of environmental toxicology due to their persistence, widespread exposure, and potential impacts on early development. At the 65th SOT Annual Meeting and ToxExpo in San Diego, a Symposium Session titled “Developmental PFAS Toxicity: Leveraging Zebrafish as a Model for Phenotypic, ’Omics, and Organ-Level Studies” highlighted how zebrafish models are advancing mechanistic understanding of PFAS toxicity. Presentations by Drs. Alicia Timme-Laragy, Subham Dasgupta, Jennifer Freeman, Nishad Jayasundara, and Drake Phelps illustrated how phenotypic screening, transcriptomics, lipidomics, and environmental exposure studies can be integrated to reveal how PFAS affect developing organs and biological pathways.
Dr. Timme-Laragy opened the session by examining how early life PFAS exposure can alter pancreatic development. Using transgenic zebrafish models, her team showed that exposure to PFOS and PFBS can disrupt the organization of pancreatic islet cells. Normally, β-cells form tightly packed clusters; however, PFAS exposure produced fragmented islet structures and abnormal pancreatic morphology. Functional changes were also observed. The exocrine pancreas appeared truncated, and enzyme production declined even at doses that did not yet produce visible structural abnormalities. Complementary single-cell RNA sequencing revealed altered gene expression related to neuronal development, xenobiotic metabolism, and oxidative stress pathways, including disrupted Nrf2 and PPAR signaling.
Dr. Dasgupta then focused on the effects of perfluorononanoic acid (PFNA) on the developing zebrafish eye and brain. Behavioral assays using alternating light-dark cycles revealed increased hyperactivity during transition periods, suggesting altered neural responses. Transcriptomic analysis of eye and brain tissues identified disruptions in pathways associated with retinol metabolism, steroid biosynthesis, and PPAR signaling. In the brain, genes involved in steroid metabolism and Notch signaling were particularly affected. Transcription factor analysis pointed to regulatory factors such as POLR1A, ESRRA, SREBF1, TFCP2, and CEBPB as potential drivers of these changes, highlighting how PFNA exposure can influence neurodevelopmental signaling networks.
Dr. Freeman’s presentation expanded the discussion to lipidomic and biochemical indicators of PFAS-induced neurotoxicity. Several PFAS compounds, including PFDA, PFOA, GenX, and PFBS, induced hyperlipidemia, whereas PFNA and PFBA were associated with hypolipidemia. Across exposure groups, increased lipid peroxidation and reactive oxygen species signaled oxidative stress, accompanied by reduced activity of antioxidant enzymes. Mitochondrial dysfunction emerged as a central mechanism: exposed zebrafish showed altered mitochondrial distribution, reduced membrane potential, and decreased ATP production. Dopaminergic signaling was also disrupted, with reduced dopamine levels and increased monoamine oxidase activity leading to elevated levels of the dopamine metabolite DOPAC.
Environmental relevance was emphasized in Dr. Jayasundara’s presentation, which started with talking about the emerging PFAS contamination in the Cape Fear River in North Carolina. Downstream concentrations near industrial discharge sites reached approximately 1,500 ng/L, far exceeding levels typically associated with legacy PFAS contamination. Some emerging ultra-short-chain PFAS revealed hepatotoxic effects and disruptions in mitochondrial bioenergetics in zebrafish models. Interestingly, transcriptomic analyses identified more differentially expressed genes at lower exposure levels than at higher concentrations, suggesting potential non-monotonic dose responses.
Closing the session, Dr. Phelps presented high-throughput screening approaches designed to address the growing number of PFAS chemicals. Using automated video-based phenotypic assays in zebrafish, his team screened more than 185 PFAS compounds across 12 developmental endpoints using computational dashboards developed by the US Environmental Protection Agency. Results showed that while some eight-carbon PFAS compounds were among the most potent, chain length alone was not a reliable predictor of toxicity.
Together, the presentations demonstrated the power of zebrafish to connect molecular mechanisms with organism-level outcomes. Zebrafish can be an excellent model to study the long-term effects of developmental PFAS toxicity by integrating phenotypic screening with multi-omics analyses.
This blog reports on the Symposium Session titled “Developmental PFAS Toxicity: Leveraging Zebrafish as a Model for Phenotypic, ’Omics, and Organ-Level Studies” that was held during the 2026 SOT Annual Meeting and ToxExpo. An on-demand recording of this session is available for meeting registrants on the SOT Online Planner and SOT Event App.
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