Identification of Pro-Atherogenic Microenvironment-Associated Molecular Signatures in Response to Key Effective PM2.5 Constituents Using a Blood–Brain Barrier-Immune Microenvironment Platform

Abstract

Fine particulate matter (PM2.5) has been associated with adverse central nervous system (CNS) outcomes, yet it remains unclear how PM2.5 constituents penetrate the blood–brain barrier (BBB) and which specific components enter the CNS to remodel the immune microenvironment. Here, we developed a human BBB-immune microenvironment platform (BBB-IMP) to model dynamic PM2.5 exposure at the BBB interface, leveraging compartment-resolved quantification of translocated constituents to elucidate the ensuing cellular cascade responses. We found that high doses of PM2.5 increase BBB permeability and promote constituent translocation into the brain side. Translocated PM2.5 induces astrocyte reactivity and microglial M1 polarization, accompanied by elevated ROS levels, neuroinflammatory responses, lipid metabolic dysregulation, and impaired barrier structural maintenance, collectively contributing to a pro-atherosclerotic microenvironment-associated molecular signature. Component-resolved correlation analysis identified chromium and the water-soluble organic matter (WSOM) fraction, particularly specific condensed organic constituents within WSOM (C28H7O2N and C21H16N2SP2), as key drivers associated with BBB impairment, glial inflammatory responses, and barrier structural disruption. This quantitative and human-relevant BBB-IMP platform provides a framework for evaluating the CNS risks of diverse complex environmental mixtures and identifying key BBB-translocating effective constituents, thereby providing evidence for future risk assessment and monitoring strategies.