Luedtke_2026_Biomolecules_16_

Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals associated with a wide range of adverse health effects, yet individual PFAS compounds may exert distinct toxicological mechanisms. In this study, we investigate the toxic effects of perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) in Drosophila melanogaster using survival assays and measurements of acetylcholinesterase (AChE) activity as indicators of systematic toxicity and neurotoxicity, respectively. Male flies were exposed to PFOA and PFNA under different feeding conditions, concentrations, and temperatures. Both compounds reduced fly viability and impaired neuronal function, but with markedly different toxicological profiles. PFNA caused a pronounced, concentration-dependent reduction in lifespan under all tested conditions, indicating a strong systemic toxicity. In contrast, PFOA exerted a comparatively weaker effect on survival but induced a more pronounced reduction in AChE activity, consistent with enhanced neurotoxicity. PFOA-induced neurotoxicity in Drosophila may represent early molecular events that predispose neurons to degeneration, contributing to conditions such as dementia. Together, these findings demonstrate that structurally similar PFAS compounds can induce distinct toxicological outcomes and highlight the importance of evaluating individual PFAS using complementary assays. Moreover, this study underscores the utility of Drosophila melanogaster as a sensitive and mechanistically informative model for dissecting compound-specific PFAS toxicity.