Penetration of Organophosphate Triesters and Diesters across the Blood-Cerebrospinal Fluid Barrier: Efficiencies, Impact Factors, and Mechanisms

The penetration of organophosphate triesters (tri- OPEs) and diesters (di-OPEs) across the blood-brain barrier and their influencing factors remain unclear in humans. In this study, 21 tri-OPEs and 8 di-OPEs were measured in 288 paired serum and cerebrospinal fluid (CSF) samples collected in Jinan, China. Six tri-OPEs were frequently detected in both serum and CSF, with median concentrations ranging from 0.062 to 1.62 and 0.042-1.11 ng/mL, respectively. Their penetration efficiencies across the blood-CSF barrier (BCSFB) (R-CSF/serum, C-CSF/C-serum) were calculated at 0.667-2.80, and these efficiencies first increased and then decreased with their log K-ow values. The reduced penetration efficiencies of triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) may be attributed to their strong binding affinities for human serum albumin and p-glycoprotein due to their high hydrophobicity and aryl structure, as indicated by molecular docking. This suggests that active efflux transport may be involved in the penetration of TPHP and EHDPP in addition to passive diffusion similar to the other four tri-OPEs. Di-OPEs were found in few serum samples and even fewer CSF samples, indicating their limited BCSFB permeability. This may be due to their high polarity, low hydrophobicity, and ionic state in blood. This study has important implications for understanding the neurotoxicity of tri-OPEs and di-OPEs and the underlying mechanisms.