Per- and polyfluoroalkyl substances and the human urinary system: Molecular mechanisms, biomarker discovery, and translational perspectives for risk mitigation.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants known for their widespread distribution and bioaccumulation. Recent studies indicate that PFAS exposure may adversely affect human urinary system health. Despite the growing body of research, a systematic understanding of their toxic mechanisms remains limited. This review evaluates the current evidence linking PFAS exposure to urinary disorders, including chronic kidney disease, acute kidney injury, and benign prostatic hyperplasia. It also highlights potential mechanisms behind PFAS toxicity, such as oxidative stress, inflammation, and activation of the PI3K-Akt signaling pathway, as well as disruption of the gut-urinary axis. PFAS accumulate in urinary organs, particularly the kidneys, through dietary intake and dermal absorption, and are transported via the bloodstream and carrier proteins. Biomarkers such as oxidative stress markers, inflammatory cytokines, kidney injury indicators, and gut microbiota profiles may offer early detection and risk assessment opportunities for PFAS-related urinary diseases. However, existing research faces challenges such as imprecise exposure assessments, incomplete understanding of toxicological pathways, and a lack of specific biomarkers. Future studies should clarify molecular mechanisms, identify reliable biomarkers, and develop targeted interventions. Enhanced environmental monitoring and evidence-based public health policies are crucial to mitigate the long-term risks of PFAS exposure.