Carbon Chain Length Determines Inhibitory Potency of Perfluoroalkyl Sulfonic Acids on Human Placental 3β-Hydroxysteroid Dehydrogenase 1: Screening, Structure-Activity Relationship, and <i>In Silico</i> Analysis.

Lu Ming Tang; Bai Ping Mao; Bing Ru Zhang; Jing Jing LI; Yun Bing Tang; Hui Tao LI; Ren Shan GE

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Carbon Chain Length Determines Inhibitory Potency of Perfluoroalkyl Sulfonic Acids on Human Placental 3β-Hydroxysteroid Dehydrogenase 1: Screening, Structure-Activity Relationship, and In Silico Analysis.

Author: Lu Ming TANG ¹ ; Bai Ping MAO ² ; Bing Ru ZHANG ² ; Jing Jing LI ² ; Yun Bing TANG ³ ; Hui Tao LI ^{3
,

4} ; Ren Shan GE ^{4
,

5}
Author Information

1. Department of Emergency Medicine, The Second Affiliated Hospital and Yuying Children Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
2. Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
3. Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China.
4. Department of Anesthesiology, The Second Affiliated Hospital and Yuying Children Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
5. Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325000, Zhejiang, China.
Publication Type:Journal Article
Keywords: 3β-hydroxysteroid dehydrogenase 1; Docking analysis; Perfluorooctanesulfonic acid; Progesterone; Structure–activity relationship
MeSH: Humans; Pregnancy; Female; Rats; Animals; Placenta; Progesterone/pharmacology*; Aromatase/pharmacology*; Cell Line, Tumor; Fluorocarbons; Alkanesulfonic Acids; Structure-Activity Relationship; Hydroxysteroid Dehydrogenases/pharmacology*
From: Biomedical and Environmental Sciences 2023;36(11):1015-1027
CountryChina
Language:English
Abstract: OBJECTIVE:This study aimed to compare 9 perfluoroalkyl sulfonic acids (PFSA) with carbon chain lengths (C4-C12) to inhibit human placental 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1), aromatase, and rat 3β-HSD4 activities.
METHODS:Human and rat placental 3β-HSDs activities were determined by converting pregnenolone to progesterone and progesterone secretion in JEG-3 cells was determined using HPLC/MS-MS, and human aromatase activity was determined by radioimmunoassay.
RESULTS:PFSA inhibited human 3β-HSD1 structure-dependently in the order: perfluorooctanesulfonic acid (PFOS, half-maximum inhibitory concentration, IC ₅₀: 9.03 ± 4.83 μmol/L) > perfluorodecanesulfonic acid (PFDS, 42.52 ± 8.99 μmol/L) > perfluoroheptanesulfonic acid (PFHpS, 112.6 ± 29.39 μmol/L) > perfluorobutanesulfonic acid (PFBS) = perfluoropentanesulfonic acid (PFPS) = perfluorohexanesulfonic acid (PFHxS) = perfluorododecanesulfonic acid (PFDoS) (ineffective at 100 μmol/L). 6:2FTS (1H, 1H, 2H, 2H-perfluorooctanesulfonic acid) and 8:2FTS (1H, 1H, 2H, 2H-perfluorodecanesulfonic acid) did not inhibit human 3β-HSD1. PFOS and PFHpS are mixed inhibitors, whereas PFDS is a competitive inhibitor. Moreover, 1-10 μmol/L PFOS and PFDS significantly reduced progesterone biosynthesis in JEG-3 cells. Docking analysis revealed that PFSA binds to the steroid-binding site of human 3β-HSD1 in a carbon chain length-dependent manner. All 100 μmol/L PFSA solutions did not affect rat 3β-HSD4 and human placental aromatase activity.
CONCLUSION:Carbon chain length determines inhibitory potency of PFSA on human placental 3β-HSD1 in a V-shaped transition at PFOS (C8), with inhibitory potency of PFOS > PFDS > PFHpS > PFBS = PFPS = PFHxS = PFDoS = 6:2FTS = 8:2FTS.