Per- and Polyfluoroalkyl Substances (PFAS) in Fruit Flies: Environmental Surveillance and Hazard Characterization of “Forever Chemicals”

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with adverse health outcomes, yet the mechanisms underlying their toxicity remain incompletely understood. This Review synthesizes current insights into PFAS toxicity derived from studies using the invertebrate model organism Drosophila melanogaster. Evidence from this model suggests that PFAS promote tumor invasion through MAPK/UPR signaling and metabolic reprogramming, disrupt metabolic homeostasis via insulin signaling and PPAR-like pathways, and induce neurotoxicity via mitochondrial dysfunction, oxidative stress, and calcium dysregulation. Both legacy PFAS (e.g., PFOA, PFOS) and emerging alternatives (e.g., GenX/HFPO-DA) perturb circadian rhythms, impair sleep–wake cycles, compromise reproduction through germ cell targeting and endocrine disruption, and delay development. Notably, low-dose exposures (≤0.05 μM; ≤0.02 μg/mL)─comparable to environmentally relevant or certain human exposure levels─can elicit subtle yet significant metabolic disturbances, circadian rhythm alterations, reduced fecundity, and transgenerational effects, implicating epigenetic mechanisms. Collectively, these findings highlight Drosophila’s value in delineating evolutionarily conserved toxicity pathways of PFAS. However, critical research gaps remain, including organ-specific limitations, mixture effects, and the need for chronic, environmentally relevant exposure paradigms to enhance translational relevance for human health.