Stage-specific disruption of host resistance and metabolic pathways following developmental PFAS exposure in marine medaka

Per- and polyfluoroalkyl substances (PFAS) are persistent contaminants with immunotoxic potential, yet impacts on immune development remain poorly defined. We examined effects of developmental PFAS exposure on host resistance and metabolism in marine medaka (Oryzias melastigma). Larvae were exposed to legacy (PFOA, PFOS) and replacement PFAS (PFHxA, PFHxS, GenX, PFBS) at 0.5 or 5 ng/mL. Exposures occurred during two immune-development windows: 7-11 days post fertilization (dpf) and 3-5 days post hatching (dph). Host resistance was measured as survival following Edwardsiella piscicida infection (Kaplan-Meier log-rank tests). Metabolic changes were profiled by metabolomics with pathway enrichment (Fisher's p < 0.05). During 7-11 dpf, PFHxA at 5 ng/mL reduced post-infection survival (p = 0.019), whereas PFOA at 0.5 ng/mL increased survival (p = 0.017). No survival differences were detected after 3-5 dph exposures. During 7-11 dpf, GenX produced the greatest number of significantly enriched pathways, including glycosphingolipid biosynthesis and sialic acid metabolism. PFOA and PFHxA were associated with disruptions involving tricarboxylic acid (TCA) intermediates, amino acid metabolism, and oxidative stress-related pathways. For 3-5 dph, only PFBS produced significant pathway enrichment, including glycerophospholipid metabolism and sialic acid metabolism. PFOS and PFHxS did not significantly alter survival or yield significant pathway enrichment under this study's conditions. Findings identify 7-11 dpf as a sensitive window of susceptibility to PFAS and show that multiple PFAS, both legacy and replacement, can alter host resistance and metabolic programs relevant to immune development in a marine teleost model.