Binding of Per- and Polyfluoroalkyl Substances to the Human Pregnane X Receptor

November 23, 2020 - Thanh T. Lai, Yiğitcan Eken, and Angela K. Wilson<akwilson@msu.edu>

Access article

Abstract

Per- and polyfluoroalkyl substances (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 overactivation. Overactivation of hPXR is linked to potential endocrine disruption, oxidative stress, 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 alternatives whose activity on hPXR has not been experimentally tested. This is the first-time MD is used to study 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 done to provide further insight. Activities on hPXR for several short-chain and alternative PFAS compounds to long-chain PFASs that have yet to be reported will also be considered. These short-chain and alternative species include perfluorobutane sulfonic acid (PFBS), Gen-X (trade name for 2,3,3,3-tetrafluoro-2-heptafluoropropoxy propanoic acid), ADONA (trade name for 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, the 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.

Authors

You Might Also Be Interested In

Accessibility Questions:

For questions about accessibility and/or if you need additional accommodations for a specific document, please send an email to ANR Communications & Marketing at anrcommunications@anr.msu.edu.

Tag List
  • pfas research

Center for PFAS Research

  • follow us on instagram
  • follow us on linkedin
Michigan State University
  • Spartans Will.
  • © Michigan State University

MSU is an affirmative-action, equal-opportunity employer, committed to achieving excellence through a diverse workforce and inclusive culture that encourages all people to reach their full potential.

Michigan State University Extension programs and materials are open to all without regard to race, color, national origin, gender, gender identity, religion, age, height, weight, disability, political beliefs, sexual orientation, marital status, family status or veteran status. Issued in furtherance of MSU Extension work, acts of May 8 and June 30, 1914, in cooperation with the U.S. Department of Agriculture. Quentin Tyler, Director, MSU Extension, East Lansing, MI 48824. This information is for educational purposes only. Reference to commercial products or trade names does not imply endorsement by MSU Extension or bias against those not mentioned.

The 4-H Name and Emblem have special protections from Congress, protected by code 18 USC 707.

We comply with the Federal Trade Commission 1998 Children’s Online Privacy Protection Act (COPPA).