Per- and polyfluoroalkyl substances inhibit human and rat 17-hydroxysteroid dehydrogenase 1: Quantitative structure-activity relationship and molecular docking analysis

Per- and polyfluoroalkyl (PFAS) substances are enduring industrial materials. 17 beta-Hydroxysteroid dehydrogenase isoform 1 (17 beta-HSD1) is an estrogen metabolizing enzyme, which transforms estrone into estradiol in human placenta and rat ovary. Whether PFAS inhibit 17 beta-HSD1 and what the structure-activity relationship (SAR) remains unexplored. We screened 18 PFAS for inhibiting human and rat 17 beta-HSD1 in microsomes and studied their SAR and mode of action(MOA). Of the 11 perfluorocarboxylic acids (PFCAs), C8-C14 PFCAs at a concentration of 100 mu M substantially inhibited human 17 beta-HSD1, with order of C11 (half-maximal inhibition concentration, IC50, 8.94 mu M) > C10 (10.52 mu M) > C12 (14.90 mu M) > C13 (30.97 mu M) > C9 (43.20 mu M) > C14 (44.83 mu M) > C8 (73.38 mu M) > others. Of the 7 per- and poly-fluorosulfonic acids (PFSAs), the potency was C8S (IC50, 14.93 mu M) > C7S (80.70 mu M) > C6S (177.80 mu M) > others. Of the PFCAs, C8-C14 PFCAs at 100 mu M markedly reduced rat 17 beta-HSD1 activity, with order of C11 (IC50, 9.11 mu M) > C12 (14.30 mu M) > C10 (18.24 mu M) > C13 (25.61 mu M) > C9 (67.96 mu M) > C8 (204.39 mu M) > others. Of the PFSAs, the potency was C8S (IC50, 37.19 mu M) > C7S (49.38 mu M) > others. In contrast to PFOS (C6S), the partially fluorinated compound 6:2 FTS with an equivalent number of carbon atoms demonstrated no inhibition of human and rat 17 beta-HSD1 activity at a concentration of 100 mu M. The inhibition of human and rat enzymes by PFAS followed a V-shaped trend from C4 to C14, with a nadir at C11. Moreover, human 17 beta-HSD1 was more sensitive than rat enzyme. PFAS inhibited human and rat 17 beta-HSD1 in a mixed mode. Docking analysis revealed that they bind to the NADPH and steroid binding site of both 17 beta-HSD1 enzymes. The 3D quantitative SAR (3D-QSAR) showed that hydrophobic region, hydrogen bond acceptor and donor are key factors in binding to 17 beta-HSD1 active sites. In conclusion, PFAS exhibit inhibitory effects on human and rat 17 beta-HSD1 depending on factors such as carbon chain length, degree of fluorination, and the presence of carboxylic acid or sulfonic acid groups, with a notable V-shaped shift observed at C11.