Transport of bisphenol analogues and their conjugated metabolites across human blood-cerebrospinal fluid barrier.

Wide presence of bisphenol analogues (BPs) and their conjugated metabolites in human blood have raised concerns about their ability to penetrate the blood-cerebrospinal fluid barrier (BCB). However, whether conjugated BP metabolites can cross the human BCB remains unclear. This study analyzed 12 BPs and 14 conjugated BP metabolites in matched serum and cerebrospinal fluid samples from 108 Chinese adults, and investigated the transport of BPs and conjugated BP metabolites across the human BCB. The findings demonstrated the ubiquitous occurrence of six conjugated BP metabolites in cerebrospinal fluid, particularly bisphenol A-glucuronide (BPA-G; mean 1.25 ng/mL, range < LOD-10.08 ng/mL), bisphenol S-sulfate (1.28 ng/mL, < LOD-9.56 ng/mL), and bisphenol S-glucuronide (BPS-G; 2.53 ng/mL, < LOD-14.64 ng/mL), with mean concentrations higher than their corresponding parent BPs. Penetration efficiencies across the BCB (RCSF/serum) were calculated for six conjugated BP metabolites, with the mean RCSF/serum values ranging from 0.16 (BPA-G) to 0.47 (BPS-G), providing the first quantitative permeability estimates for these compounds in humans. Furthermore, the RCSF/serum values of the six conjugated BP metabolites showed a negative (p < 0.01) correlation with their lipophilicity (i.e., log Kow values). RCSF/serum values were also positively (p < 0.05) correlated with the BCB permeability index Ralb (i.e., cerebrospinal fluid/serum albumin ratio). These data suggest that chemical lipophilicity and BCB integrity are important determinants of BCB penetration for conjugated BP metabolites. These findings advance the understanding of human internal exposure to BPs and their conjugated metabolites within the central nervous system, and provide critical insights into their potential neurotoxic effects in humans.