Per- and Polyfluoroalkyl Substances Can Induce Immunotoxicity via Direct Intestinal Lymphatic Absorption

Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants with immunotoxicity as a primary health concern. Their in vivo fate has long been interpreted within a blood-centric toxicokinetic framework, whereas the lymphatic system, a key immune surveillance hub, has been overlooked as an exposure compartment. Given their structural similarity to long-chain fatty acids, PFAS may be absorbed via intestinal lymphatics, directly exposing resident immune cells, a hypothesis never experimentally verified. Here, using rat models with mesenteric lymph duct and jugular vein cannulation, and in vitro assays, we systematically characterized PFAS lymphatic absorption, distribution, and immunotoxicological relevance. We provide direct evidence that PFAS enter mesenteric lymph, with concentrations reaching 27-116% of serum levels within 10 h. Intestinal lymphatic absorption and subsequent return to the bloodstream significantly prolonged PFAS half-lives and altered their exposure profiles. Circulating PFAS redistributed into the lymphatic network via interstitial fluid and selectively accumulated in lymph nodes. In vitro, environmentally relevant PFAS concentrations (ng/mL) significantly impaired monocyte differentiation and function, highlighting immunotoxic significance of lymphatic exposure. This study establishes the lymphatic system as a long-neglected, essential compartment in PFAS toxicokinetics, underscoring the need to incorporate lymphatic exposure into health risk assessments of PFAS and other persistent pollutants.