Perfluorohexanesulfonic\nAcid (PFHxS) Impairs Lipid\nHomeostasis in Zebrafish Larvae through Activation of PPARα

Perfluorohexanesulfonic acid (PFHxS), an emerging short-chain\nper-\nand polyfluoroalkyl substance, has been frequently detected in aquatic\nenvironments. Adverse outcome pathway studies have shown that perfluorinated\ncompounds impair lipid homeostasis through peroxisome proliferator\nactivated receptors (PPARs). However, many of these studies were performed\nat high concentrations and may thus be a result of overt toxicity.\nTo better characterize the molecular and key events of PFHxS to biota,\nearly life-stage zebrafish (Danio rerio) were exposed to concentrations detected in the environment (0.01,\n0.1, 1, and 10 μg/L). Lipidomic and transcriptomic evaluations\nwere integrated to predict potential molecular targets. PFHxS significantly\nimpaired lipid homeostasis by the dysregulation of glycerophospholipids,\nfatty acyls, glycerolipids, sphingolipids, prenol lipids, and sterol\nlipids. Informatic analyses of the lipidome and transcriptome indicated\nalterations of the PPAR signaling pathway, with downstream changes\nto retinol, linoleic acid, and glycerophospholipid metabolism. To\nassess the role of PPARs, potential binding of PFHxS to PPARs was\npredicted and animals were coexposed to a PPAR antagonist (GW6471).\nMolecular simulation indicated PFHxS had a 27.1% better binding affinity\nthan oleic acid, an endogenous agonist of PPARα. Antagonist\ncoexposures rescued impaired glycerophosphocholine concentrations\naltered by PFHxS. These data indicate PPARα activation may be\nan important molecular initiating event for PFHxS.