PMID- 29248446 OWN - NLM STAT- MEDLINE DCOM- 20180129 LR - 20180129 IS - 1872-7786 (Electronic) IS - 0009-2797 (Linking) VI - 281 DP - 2018 Feb 1 TI - Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) - A comparison with lysosomotropic drugs. PG - 1-10 LID - S0009-2797(17)31013-X [pii] LID - 10.1016/j.cbi.2017.12.021 [doi] AB - Many chemicals accumulate in organisms through a variety of different mechanisms. Cationic amphiphilic drugs (CADs) accumulate in lysosomes and bind to membranes causing phospholipidosis, whereas many lipophilic chemicals target adipose tissue. Perfluoroalkyl substances (PFASs) are widely used as surfactants, but many of them are highly bioaccumulating and persistent in the environment, making them notorious environmental toxicants. Understanding the mechanisms of their bioaccumulation is, therefore, important for their regulation and substitution with new, less harmful chemicals. We compared the highly bioaccumulative perfluorooctanesulfonic acid PFOS to its three less bioaccumulative alternatives perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutane sulfonic acid (PFBS), in their ability to accumulate and remain in lung epithelial cells (NCI-H292) and adipocytes (3T3-L1K) in vitro. As a reference point we tested a set of cationic amphiphilic drugs (CADs), known to highly accumulate in cells and strongly bind to phospholipids, together with their respective non-CAD controls. Finally, all compounds were examined for their ability to bind to neutral lipids and phospholipids in cell-free systems. Cellular accumulation and retention of the test compounds were highly correlated between the lung epithelial cells and adipocytes. Interestingly, although an anion itself, intensities of PFOS accumulation and retention in cells were comparable to those of CAD compounds, but PFOS failed to induce phospholipidosis or alter lysosomal volume. Compared to other lipophilicity measures, phospholipophilicity shows the highest correlation (R^2 = 0.75) to cellular accumulation data in both cell types and best distinguishes between high and low accumulating compounds. This indicates that binding to phospholipids may be the most important component in driving high cellular accumulation in lung epithelial cells, as well as in adipocytes, and for both CADs and bioaccumulating PFASs. Obtained continuous PLS models based on compound's affinity for phospholipids and neutral lipids can be used as good prediction models of cellular accumulation and retention of PFASs and CADs. CI - Copyright (c) 2017 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Sanchez Garcia, Diana AU - Sanchez Garcia D AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Sjodin, Marcus AU - Sjodin M AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Hellstrandh, Magnus AU - Hellstrandh M AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Norinder, Ulf AU - Norinder U AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Nikiforova, Violetta AU - Nikiforova V AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Lindberg, Johan AU - Lindberg J AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Wincent, Emma AU - Wincent E AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Bergman, Ake AU - Bergman A AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Cotgreave, Ian AU - Cotgreave I AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. FAU - Munic Kos, Vesna AU - Munic Kos V AD - Swetox, Karolinska Institutet, Unit of Toxicology Sciences, Forskargatan 20, SE-151 36 Sodertalje, Sweden. Electronic address: vesna.munic.kos@swetox.se. LA - eng PT - Journal Article DEP - 20171214 PL - Ireland TA - Chem Biol Interact JT - Chemico-biological interactions JID - 0227276 RN - 0 (Alkanesulfonic Acids) RN - 0 (Caproates) RN - 0 (Caprylates) RN - 0 (Cations) RN - 0 (Fluorocarbons) RN - 0 (Lipids) RN - 0 (Pharmaceutical Preparations) RN - 0 (Phospholipids) RN - 0 (Sulfonic Acids) RN - 0 (perfluorobutanesulfonic acid) RN - 83905-01-5 (Azithromycin) RN - 947VD76D3L (perfluorooctanoic acid) RN - 9H2MAI21CL (perfluorooctane sulfonic acid) RN - ZP34Q2220R (perfluorohexanoic acid) SB - IM MH - Adipocytes/cytology/metabolism MH - Alkanesulfonic Acids/chemistry/*metabolism MH - Animals MH - Azithromycin/chemistry/metabolism MH - Caproates/chemistry/metabolism MH - Caprylates/chemistry/metabolism MH - Cations/chemistry MH - Cell Line MH - Cell Survival MH - Epithelial Cells/cytology/metabolism MH - Fluorocarbons/chemistry/*metabolism MH - Humans MH - Least-Squares Analysis MH - Linear Models MH - Lipids/chemistry MH - Lysosomes/*metabolism MH - Mice MH - Pharmaceutical Preparations/chemistry/*metabolism MH - Phospholipids/chemistry/*metabolism MH - Sulfonic Acids/chemistry/metabolism OTO - NOTNLM OT - Adipocytes OT - Bioaccumulation OT - Cationic amphiphilic drugs OT - PFOS OT - Perfluorinated compounds OT - Phospholipid binding EDAT- 2017/12/19 06:00 MHDA- 2018/01/30 06:00 CRDT- 2017/12/18 06:00 PHST- 2017/09/29 00:00 [received] PHST- 2017/11/07 00:00 [revised] PHST- 2017/12/13 00:00 [accepted] PHST- 2017/12/19 06:00 [pubmed] PHST- 2018/01/30 06:00 [medline] PHST- 2017/12/18 06:00 [entrez] AID - S0009-2797(17)31013-X [pii] AID - 10.1016/j.cbi.2017.12.021 [doi] PST - ppublish SO - Chem Biol Interact. 2018 Feb 1;281:1-10. doi: 10.1016/j.cbi.2017.12.021. Epub 2017 Dec 14.