Insights into CD36/P-gp involvement in dietary lipid-driven PAH transport across the blood-brain barrier

Polycyclic aromatic hydrocarbons (PAHs), as widespread environmental contaminants, exhibit neurotoxicity. Because PAHs often co-occur with dietary lipids in foods, those lipids might serve as vehicles that alter PAH biotransport and accumulation in the brain. In this work, we systematically investigated how three common dietary fatty acids-oleic acid, linoleic acid (LA), and linolenic acid-differently influence the transport steps (including cellular uptake, efflux, and clearance) of benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF) across the blood-brain barrier, using a bEnd.3 cell-based model, and explored the potential underlying molecular mechanisms. Results revealed that dietary lipids, acting as carriers, significantly enhanced cellular uptake of PAHs, with LA increasing the uptake of BaP and BbF by 20.36% and 17.90%, respectively, and accelerated transmembrane transport dynamics. Simultaneously, distinct lipids differentially affected PAH clearance and efflux. Notably, LA delayed the clearance of PAHs, prolonging the elimination half-life of BaP from 10.117 h to 17.696 h and that of BbF from 7.418 h to 14.964 h, thereby increasing overall brain exposure. Mechanistically, LA was observed to upregulate the fatty acid transporter CD36, and functional inhibition studies suggested that P-glycoprotein and CD36 may jointly contribute to lipid-modulated effects. This study suggests that dietary lipids influence brain exposure to PAHs through a multi-level network, highlighting a factor that warrants consideration when assessing their neurotoxicity risks.