Perfluoroalkyl substances and immunotoxicity: An in vitro structure-activity relationship study in THP-1-derived monocytes and macrophages.

Recently, PFASs toxicity for the human immune system has become a growing concern. However, there is currently limited information on PFASs immunotoxicity beyond PFHxS, PFOA, PFOS, and PFNA. Therefore, it is urgent to close the present knowledge gap by testing a wider range of compounds. In the present study, twelve compounds were tested for a relationship between the chain-length and headgroup of a PFAS and its cytotoxic for THP-1. As such, THP-1, either as monocytes or differentiated macrophages, were exposed to PFASs in a concentration range of 0-800 μM for either 3 or 24 h. After that, cell viability and reactive oxygen species (ROS) generation were assessed using MTT and DCFH assay, respectively. PFASs' cytotoxicity is dependent on both their chain-length and headgroups. Cell viability decreased with increasing chain-length, and FTOHs displayed markedly higher toxicity than PFCAs and PFSAs. PFASs were ranked based on their calculated Relative Potency Factor. The ranking for the cytotoxicity data on monocytes appears to be 6:2 FTOH ≫ PFNA > PFDA > PFOS > PFOA >4: 2 FTOH > PFHxS = PFHxA > PFBA. For macrophages, this ranking was as follows: 6:2 FTOH >4:2 FTOH > PFOS > PFDA > PFNA > PFOA > PFHxS. The results observed for the ROS generating potential differed as FTOHs generated no ROS. Here, the ranking in monocytes was PFOA > PFNA > PFOS > PFHxS > PFDA > PFHxA = PFBS = PFBA. The ranking for macrophages was PFNA > PFDA ≥ PFOA > PFOS > PFHxA > PFHxS > PFBA = PFBS. In conclusion, the carbon chain-length and functional headgroup of a PFAS are major determinants for their toxicity to THP-1 cells. Furthermore, our study demonstrates the most potent cytotoxic effect for FTOHs in vitro, which has not been observed before to the authors' knowledge.