The Vitamin D Receptor as a Potential Target for the Toxic Effects of Per-and Polyfluoroalkyl Substances (PFASs)

By Ettayapuram Ramaprasad Azhagi Singam, Kathleen A. Durkin, Michele A. La Merrill, David J. Furlow, Jen-Chywan Wang, and Martyn T. Smith
SSRN
June 21, 2022
DOI: 10.2139/ssrn.4141923

Due to their persistence and toxicity, perfluoroalkyl and polyfluoroalkyl substances (PFASs) constitute a significant hazard to human health and the environment. Their effects include immune suppression, altered hormone levels and osteoporosis. Recently, the most studied PFAS, perfluorooctanoic acid (PFOA), was shown to competitively binding to the Vitamin D receptor (VDR). VDR plays a key role in regulating genes involved in maintaining immune, endocrine and calcium homeostasis, suggesting it may be a target for at least some of the health effects of PFAS. Hence, in this study the potential binding of 5,254 PFASs to VDR was examined using molecular docking, molecular dynamics and free energy binding calculations. We identified 14 PFAS that are predicted to strongly interact with VDR similar to the natural ligands. We further investigated the interactions of VDR with 256 PFASs of established commercial importance. Eighty-two (32%) of these 256 commercially important PFAS were predicted to be stronger binders to VDR than PFOA. At least 16 PFASs of regulatory importance, because they have been identified in water supplies and human blood samples, were also more potent binders to VDR than PFOA. Further, PFASs are usually found together in contaminated drinking water and human blood samples which raises the concern that multiple PFASs may act together as a mixture on VDR function, potentially producing their harmful effects on immune, endocrine and bone homeostasis.

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