Session: COMP Poster Session:

Per-and poly-fluoroalkylsubstances (PFASs) are a class of environmentally persistent industrial compounds that disrupt various metabolic pathways. Among the protein receptors to which PFASs bind, the human Pregnane X Receptor (hPXR) is found to be a host for a variety of long and short chain PFASs that lead to its over-activation. Over-activation of hPXR is linked to potential endocrine disruption, oxidativestress, hepatic steatosis,and adverse drug interactions. In this study, molecular dynamics (MD) is used to study the binding between hPXR and a number of PFAS compounds, including perfluorooctanoic acid (PFOA)and perfluorooctane sulfonic acid (PFOS) alternatives whose activity on hPXR has not been experimentally tested. In this study, MD is used to investigate the interactions between PFASs and hPXR, showing how relative binding free energies of PFASs relate to hPXR agonism. Binding free energy calculations, hydrogen bond analysis, per-residue decomposition calculations,and alanine scanning studies are doneto provide further insight. Activities on hPXR for several short-chain alternative PFAScompounds to long-chain PFASs that have yet to be reported will also be considered. These short-chain species include perfluorobutanesulfonicacid (PFBS), Gen-X(trade namefor 2,3,3,3-tetrafluoro-2-heptafluoropropoxy propanoicacid), ADONA(trade namefor 4,8-dioxa-3H-perfluorononanoic acid) and 6:2 fluorotelomer carboxylic acid (6:2 FTCA). The study shows key aspects of PFAS recognition on the hPXR, link between PFAS binding to hPXR and the hPXR activity change observed upon the PFAS exposure,and the potential effects of alternative PFASs on hPXR activity.

Lai Thanh

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