Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)

• DOI: 10.1016/j.envint.2022.107203
• Publication Date: 2022-03-29T17:52:10Z
• Authors: Sofie Søderstrøm; Roger Lille-Langøy; Fekadu Yadetie; Mateusz Rauch; Ana Milinski; Annick Dejaegere; Roland H. Stote; Anders Goksøyr; Odd André Karlsen
• Keywords: Docking (animal)

Toxicity mediated by per- and polyfluoroalkyl substances (PFAS), especially perfluoroalkyl acids (PFAAs), has been linked to activation of peroxisome proliferator-activated receptors (Ppar) in many vertebrates. Here, we present the primary structures, phylogeny, tissue-specific distributions Atlantic cod (Gadus morhua) gmPpara1, gmPpara2, gmPparb, gmPparg, demonstrate that carboxylic PFHxA, PFOA, PFNA, as well sulfonic acid PFHxS, activate gmPpara1 vitro, which was also supported silico analyses. Intriguingly, a binary mixture PFOA non-activating PFOS produced higher compared alone, suggesting potentiating effect on receptor activation. Supporting experimental data, docking molecular dynamics simulations single double-ligand complexes led identification putative allosteric binding site, upon stabilizes an active conformation gmPpara1. Notably, exposures gmPparb model-agonists PFAAs similar effects. This study provides novel mechanistic insights into how may modulate Ppar signaling pathway either canonical ligand-binding pocket or interacting with site. Thus, individual PFAAs, mixtures, could potentially Ppar-signaling interfering at least one gmPpar subtype.