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

Abstract

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.

Pervasive environmental chemicals impair oligodendrocyte development

“…We show that the organophosphate flame retardant TDCIPP arrests the development of mouse oligodendrocytes and inhibits oligodendrocyte generation in human cortical organoids at concentrations similar to estimated blood concentrations in children 46 . Our results and the likelihood of organophosphate flame retardant exposure in children raise potential health concerns as these chemicals may reach higher concentrations in cerebrospinal fluid than blood 47 .…”

“…The pervasive use of organophosphate flame retardants has contaminated the environment and increased human exposure, demonstrated by the detection of these chemicals in human blood, urine, breast milk, and cerebrospinal fluid 44,45 . We show that the organophosphate flame retardant TDCIPP arrests the development of mouse oligodendrocytes and inhibits oligodendrocyte generation in human cortical organoids at concentrations similar to estimated blood concentrations in children 46 .…”

Integrating Physiologically Based Pharmacokinetic Modeling-Based Forward Dosimetry and in Vitro Bioassays to Improve the Risk Assessment of Organophosphate Esters on Human Health

“…Additionally, the appropriate physicochemical properties of TCIPP (i.e., molecular weight of 328 Da, molecular volume of 265 Å 3 /molecule, and lipophilicity log K ow of 2.59) may promote its passive diffusion in blood-rich organs. Moreover, its low binding affinities with efflux transporters, such as P-glycoprotein (−4.9 kcal/mol), may inhibit TCIPP efflux from these organs . These reasons altogether resulted in the accumulation of TCIPP in the human liver and kidney.…”

“…Moreover, its low binding affinities with efflux transporters, such as Pglycoprotein (−4.9 kcal/mol), may inhibit TCIPP efflux from these organs. 66 These reasons altogether resulted in the accumulation of TCIPP in the human liver and kidney. Similarly, it has been reported that TCIPP can cross the blood−cerebrospinal fluid barrier and accumulate in the cerebrospinal fluid with the highest penetration efficiencies (median = 2.80) among target OPEs 67 .…”

Percutaneous Penetration of Liquid Crystal Monomers (LCMs) by In Vitro Three-Dimensional Human Skin Equivalents: Possible Mechanisms and Implications for Human Dermal Exposure Risks

“…Molecular Docking was widely used for estimating the binding affinities of the chemical transporter for classifying and screening for active ligands of environmental contaminants. − Membrane transport proteins in humans are largely composed of two families: ATP binding cassette (ABC) and solute carrier (SLC) transporters. , ABC transporters are active transporters and utilize the energy of ATP binding and hydrolysis to facilitate in- or efflux of their substrates across membranes. On the other hand, SLC transporters utilize ion electrochemical gradients, such as sodium or proton gradients for the uphill transport of the substrates .…”