Interactions of Perfluorooctanesulfonate and 6:2 Chlorinated Polyfluorinated Ether Sulfonate with Human Serum Albumin: A Comparative Study

Abstract

6:2 Chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) possesses a similar structure to perfluorooctanesulfonate (PFOS) and is the third most important polyfluoroalkyl/perfluoroalkyl substance (PFAS) found in the general population of China. Studies have indicated that 6:2 Cl-PFESA exhibits a stronger bioaccumulative and toxicological potential than PFOS and is thus of considerable environmental concern. Here, the binding characteristics of PFOS and 6:2 Cl-PFESA to human serum albumin (HSA) were explored based on in vitro and in silico methods. In the cell uptake assays, supplementation of HSA in the culture medium hindered diffusion of PFOS and 6:2 Cl-PFESA from the medium into cells. With the addition of 0.5, 10, and 200 μM HSA in the culture medium, the PFOS concentration in cells decreased by 21.4%, 78.1%, and 92.8%, whereas the 6:2 Cl-PFESA concentration in cells decreased by 28.4%, 84.4%, and 93.9%, respectively. Although no statistically significant difference between the reduction of PFOS and 6:2 Cl-PFESA was observed with 200 μM HSA in medium, the significant decrease in cellular 6:2 Cl-PFESA than PFOS after addition of 0.5 and 10 μM HSA implied that 6:2 Cl-PFESA had a stronger binding affinity than PFOS to HSA. Ultrafiltration centrifugation also suggested that 6:2 Cl-PFESA (K d = 16.7 μM) had a higher affinity than PFOS (K d = 30.7 μM) to HSA, though the binding molar ratios were similar, with 1 M HSA binding to 3–4 M PFOS/6:2 Cl-PFESA. Limited proteolysis further identified the core HSA peptides that bind to PFOS (peptide II, aa 189–457) and 6:2 Cl-PFESA (peptide I, aa 39–310). Using purified core peptides, 6:2 Cl-PFESA showed a stronger binding affinity than PFOS to both peptides I and II. The binding modes indicated that the chlorine and oxygen atoms in 6:2 Cl-PFESA were likely responsible for its preferential binding to Sudlow site I than to Trp214 or Sudlow site II, with the latter being the optimal binding site for PFOS. Overall, the stronger binding affinity of 6:2 Cl-PFESA to HSA may contribute to its higher bioaccumulation potential than PFOS.

Temporal Trends in Prenatal Exposure (1998–2018) to Emerging and Legacy Per- and Polyfluoroalkyl Substances (PFASs) in Cord Plasma from the Beijing Cord Blood Bank, China

“…65 In addition, 6:2 Cl-PFESA can induce liver enlargement, injury and disturb lipid metabolism at low doses, and can bind to human serum albumin with stronger affinity compared with PFOS. 66 Significant positive correlations between PFASs were observed, especially PFHxS-PFHpS, PFHxS-PFOS, and PFHpS-PFOS, from 1998 to 2008. In addition, 8:2 Cl-PFESA, as an impurity of 6:2 Cl-PFESA production, 67 was positively correlated with 6:2 Cl-PFESA in 1998−2008.…”

“…Animal studies have shown that environmentally relevant concentrations of 6:2 Cl-PFESA can decrease the heart rate in avian embryos and enlarge liver mass in hatchings . In addition, 6:2 Cl-PFESA can induce liver enlargement, injury and disturb lipid metabolism at low doses, and can bind to human serum albumin with stronger affinity compared with PFOS . Significant positive correlations between PFASs were observed, especially PFHxS-PFHpS, PFHxS-PFOS, and PFHpS-PFOS, from 1998 to 2008.…”

Effect of Enterohepatic Circulation on the Accumulation of Per- and Polyfluoroalkyl Substances: Evidence from Experimental and Computational Studies

“…This may be due to the complexity of the multiple binding sites and the flexible conformations of different pockets for the binding of the ligand to HSA. Recently, Sheng et al proposed that PFOS and 6:2 Cl-PFESA, an alternative of PFOS, showed preferential binding to different binding sites of HSA based on the binding measure of designed core peptides. Therefore, the use of single conformation of complexes, such as the crystal structure of PFOS-HSA (PDB ID: 4E99), may be insufficient to rank the binding strength of mixed linear and nonlinear PFAS based on the docking score evaluations in Sudlow site II in subdomain IIIA (fatty acid 3/4 site), although this site has been demonstrated to be a major binding site for linear PFOS in the previous reports. , …”

Associations of per‐ and polyfluoroalkyl substance concentrations in the blood of Amur tigers and physiological parameters

“…6:2 Cl‐PFESA was a substitute for PFOS and may have more potent reproductive toxicity that affected the birth weight of newborns (Chu et al, 2020); it was related to reduced hepatitis B virus surface antibody levels in adults, and it can cause liver damage in mammals (Wang et al, 2020; Zeng et al, 2020). Moreover, the ability of 6:2 Cl‐PFESA to bind to serum protein was stronger than that of PFOS (Sheng et al, 2020). In our results, it was not difficult to discover that 6:2 Cl‐PFESA has always been negatively correlated with immune cells (WBCs, LYMs, MONs, NEUs).…”