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Per- and polyfluoroalkyl (PFAS) substances are a large group of chemicals with elevated water and oil-resistance properties, widely implicated in various applicative fields. Due to the extensive use and high resistance to degradative factors, these compounds pose a significant risk of environmental spreading, bioaccumulating also in living organisms. In this context, despite many researches have been performed to demonstrate "legacy" PFAS harmfulness, only few data are still available about all the emerging fluorinated molecules, industrially introduced to replace the previous ones. For this reason, we proposed the medicinal leech Hirudo verbana as consolidated invertebrate model to assess the effects of four different PFAS (HFPO-DA, PFMoBa, PFOA and PFMOPrA) following freshwater dispersion. Morphological, immunohistochemical and molecular analyses demonstrate that, despite all the compounds basically induce an acute inflammatory and oxidative stress response, a different cellular and molecular response has been observed. Whereas for PFOA and PFMOPrA an increase in the tested concentration leads to a corresponding rise in the immune response, HFPO-DA and PFMoBa trigger an entirely opposite effect. Indeed, the significant recruitment of both granulocytes and macrophage like cells, typically involved in the removal of non-self, is inhibited with increasing concentrations of these compounds. The data collected revealed a different sensitivity of the leech immune system following PFAS exposure, requiring to deepen the current knowledge on the potential toxicity of these compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)