PFAS-induced blood-brain barrier dysfunction: A neurovascular perspective

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants widely detected in human circulation, yet their neurotoxic mechanisms remain incompletely understood. Emerging evidence suggests that the blood-brain barrier (BBB) may represent an important site of PFAS interaction alongside the brain parenchyma. Cerebral endothelial cells are continuously exposed to circulating PFAS, which has been associated with oxidative stress, inflammatory activation, alterations in tight junction organization, and increased barrier permeability. Although these effects may occur without extensive endothelial cell death or gross structural damage to the vascular architecture, most currently available PFAS studies report measurable molecular or functional alterations of the BBB. Direct evidence for neurovascular signaling in the complete absence of detectable barrier dysfunction remains limited. Here, we propose a neurovascular framework in which PFAS-induced endothelial dysfunction may trigger signaling cascades that propagate across the neurovascular unit (NVU), affecting pericytes, astrocytes, and microglia. This propagation can be understood as a coordinated, multiscale process influenced by endothelial signaling rather than direct neuronal exposure alone, potentially contributing to a self-reinforcing cycle of neurovascular dysfunction. This perspective highlights an interface-driven mechanism centered on the BBB, complementing existing parenchyma-focused models. Despite increasing support for this framework, critical gaps remain. Most mechanistic evidence is derived from a limited subset of legacy PFAS, particularly PFOS and PFOA, raising concerns regarding generalizability to emerging compounds. In addition, existing experimental models often fail to capture the multicellular complexity and chronic exposure conditions relevant to human physiology. Addressing these limitations will require the development of human-relevant neurovascular models capable of resolving endothelial responses and their downstream effects. Collectively, this framework provides a conceptual basis for linking chronic low-dose PFAS exposure to neurovascular dysfunction and supports the development of more human-relevant risk assessment strategies.