Novel insights into the mediating roles of cluster of differentiation 36 in transmembrane transport and tissue partition of per- and polyfluoroalkyl substances in mice.

Transmembrane transport is important for bioaccumulation of per- and polyfluoroalkyl substances (PFASs) in organisms, but has not yet been well understood. Here, the roles of cluster of differentiation 36 (CD36) in accumulation of PFASs were investigated. CD36 was overexpressed in Escherichia coli to get CD36-BL21 strain, and the binding affinities of 20 PFASs with CD36 were determined by microscale thermophoresis, which grew up to 17.5 µM with increasing carbon chain length. Consequently, the accumulation of most PFASs was remarkably promoted in CD36-BL21 in comparison to the wild strain, and the enhancement was proportional to their binding affinities with CD36 (r = -0.96). However, this effect was depressed greatly as CD36 was inhibited by sulfo-N-succinimidyl oleate (SSO). Additionally, as the mice received SSO pretreatment before they were exposed to perfluorododecanoic acid, its accumulation in the tissues rich in CD36, such as liver, was suppressed, but increased by 1.1 times in the serum. These indicated that CD36 played critical roles in the transmembrane transport and tissue partition of PFASs in organisms. The developed relationship between liver-blood partition of PFASs and their binding affinities with intracellular proteins was distinctly improved by incorporating that with CD36 (r = -0.97).

Insights into the Competitive Mechanisms of Per- and Polyfluoroalkyl Substances Partition in Liver and Blood.

Some per- and polyfluoroalkyl substances (PFASs) tend to be accumulated in liver and cause hepatotoxicity. However, the difficulty to directly measure liver concentrations of PFASs in humans hampers our understanding of their hepatotoxicity and mechanisms of action. We investigated the partitioning of 11 PFASs between liver and blood in male CD-1 mice. Although accumulation of the perfluoroalkanesulfonic acids (PFSAs) in mice serum was higher than their carboxylic acids (PFCAs) counterparts as expected, the liver-blood partition coefficients (RL/S) of PFSAs were lower than the PFCAs RL/S, implying a competition between liver and blood. The in vitro experiments further indicated that the partitioning was dominantly determined by their competitive binding between human liver fatty acid binding protein (hL-FABP) and serum albumin (HSA). The binding affinities (Kd) of PFASs to both proteins were measured. The correlations between the RL/S and log Kd (hL-FABP)/log Kd (HSA) were stronger than those with log Kd (hL-FABP) alone, magnifying that the partitioning was dominantly controlled by competitive binding between hL-FABP and HSA. Therefore, the liver concentrations of the selected PFASs in humans could be predicted from the available serum concentrations, which is important for assessing their hepatotoxicity.