Abstract：
Per- and polyfluoroalkyl (PFAS) substances are enduring industrial materials. 17β-Hydroxysteroid dehydrogenase isoform 1 (17β-HSD1) is an estrogen metabolizing enzyme, which transforms estrone into estradiol in human placenta and rat ovary. Whether PFAS inhibit 17β-HSD1 and what the structure-activity relationship (SAR) remains unexplored. We screened 18 PFAS for inhibiting human and rat 17β-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 μM substantially inhibited human 17β-HSD1, with order of C11 (half-maximal inhibition concentration, IC50, 8.94 μM) > C10 (10.52 μM) > C12 (14.90 μM) > C13 (30.97 μM) > C9 (43.20 μM) > C14 (44.83 μM) > C8 (73.38 μM) > others. Of the 7 per- and poly-fluorosulfonic acids (PFSAs), the potency was C8S (IC50, 14.93 μM) > C7S (80.70 μM) > C6S (177.80 μM) > others. Of the PFCAs, C8-C14 PFCAs at 100 μM markedly reduced rat 17β-HSD1 activity, with order of C11 (IC50, 9.11 μM) > C12 (14.30 μM) > C10 (18.24 μM) > C13 (25.61 μM) > C9 (67.96 μM) > C8 (204.39 μM) > others. Of the PFSAs, the potency was C8S (IC50, 37.19 μM) > C7S (49.38 μM) > 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 17β-HSD1 activity at a concentration of 100 μM. 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 17β-HSD1 was more sensitive than rat enzyme. PFAS inhibited human and rat 17β-HSD1 in a mixed mode. Docking analysis revealed that they bind to the NADPH and steroid binding site of both 17β-HSD1 enzymes. The 3D quantitative SAR (3D-QSAR) showed that hydrophobic region, hydrogen bond acceptor and donor are key factors in binding to 17β-HSD1 active sites. In conclusion, PFAS exhibit inhibitory effects on human and rat 17β-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.
摘要：
全氟烷基和多氟烷基(PFAS)物质是持久的工业材料。17β-羟基类固醇脱氢酶亚型1（17β-HSD1）是一种雌激素代谢酶，将人胎盘和大鼠卵巢中的雌酮转化为雌二醇。PFAS是否抑制17β-HSD1以及什么结构-活性关系(SAR)仍有待探索。我们筛选了18种PFAS，用于抑制微粒体中的人和大鼠17β-HSD1，并研究了它们的SAR和作用方式（MOA）。在11种全氟羧酸(PFCA)中，浓度为100μM的C8-C14PFCAs基本上抑制人17β-HSD1，程度为C11（半最大抑制浓度，IC50,8.94μM)>C10(10.52μM)>C12(14.90μM)>C13(30.97μM)>C9(43.20μM)>C14(44.83μM)>C8(73.38μM)>其他。在7种全氟磺酸和多氟磺酸(PFSA)中，效价为C8S（IC50，14.93μM）>C7S（80.70μM）>C6S（177.80μM）>其他。在PFCA中,100μM的C8-C14PFCA显着降低了大鼠17β-HSD1活性，顺序为C11（IC50，9.11μM）>C12（14.30μM）>C10（18.24μM）>C13（25.61μM）>C9（67.96μM）>C8（204.39μM）>其他。在PFSA中，效价为C8S（IC50，37.19μM）>C7S（49.38μM）>其他。与全氟辛烷磺酸(C6S)相比，具有相等碳原子数的部分氟化的化合物6:2FTS在100μM的浓度下显示对人和大鼠17β-HSD1活性没有抑制。PFAS对人和大鼠酶的抑制作用从C4到C14呈V形趋势，最低点在C11。此外，人17β-HSD1比大鼠酶更敏感。PFAS以混合模式抑制人和大鼠17β-HSD1。对接分析显示它们与两种17β-HSD1酶的NADPH和类固醇结合位点结合。三维定量SAR(3D-QSAR)显示,氢键受体和供体是与17β-HSD1活性位点结合的关键因素。总之,PFAS对人和大鼠17β-HSD1表现出抑制作用，具体取决于碳链长度等因素，氟化程度,以及羧酸或磺酸基团的存在，在C11处观察到明显的V形移位。
