Penetrating potential evaluation of cyclotriphosphazenes target blood-brain barrier via computational toxicology...

Cyclotriphosphazenes (CTPs), widely used as lithium-ion battery electrolyte additives, are increasingly recognized as environmental contaminants with potential neurotoxicity. We developed an integrated computational framework to evaluate the blood-brain barrier (BBB) penetration potential and neurotoxic mechanisms of CTPs. Six representative CTPs were predicted to penetrate the BBB via passive diffusion and impair BBB function. Among them, HPCTP, PFPCTP, HCCTP, and HFCTP primarily disrupted BBB function through inhibition of ATP-binding cassette transporters. HPCTP exhibited the strongest BBB-disrupting potential, primarily through interactions with SLC2A1 and SLC6A3 and through the modulation of BBB-related gene expression. Experimental validation in hCMEC/D3 cells showed that HPCTP impaired glucose transport and utilization and significantly downregulated SLC2A1 expression. These findings provide a strategy for assessing BBB penetration of exogenous chemicals and highlight the potential CNS risks associated with environmental CTP exposure.