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

Chao Wen; Huan Chen; Yunbing Tang; Hang Lin; Congcong Xu; Yingfen Ying; Yang Zhu; Xinjun Miao; Ren-shan Ge; Chao Chen; Shangqin Chen

Ecotoxicology and Environmental Safety (Mar 2024)

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

Chao Wen,
Huan Chen,
Yunbing Tang,
Hang Lin,
Congcong Xu,
Yingfen Ying,
Yang Zhu,
Xinjun Miao,
Ren-shan Ge,
Chao Chen,
Shangqin Chen

Affiliations

Chao Wen: Department of Neonatal Paediatrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Huan Chen: Department of Emergency, the Dingli Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Yunbing Tang: Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Hang Lin: Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children’s Hospital, Key Laboratory of Pediatric Anesthesiology, Ministry of Education; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Congcong Xu: Department of Neonatal Paediatrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Yingfen Ying: Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
Yang Zhu: Key Laboratory of Structural Malformations in Children of Zhejiang Province and Key Laboratory of Male Health and Environment of Wenzhou, Zhejiang Province 325000, China
Xinjun Miao: Department of Emergency, the Dingli Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Ren-shan Ge: Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children’s Hospital, Key Laboratory of Pediatric Anesthesiology, Ministry of Education; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province and Key Laboratory of Male Health and Environment of Wenzhou, Zhejiang Province 325000, China; Corresponding author at: Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Chao Chen: Department of Neonatal Paediatrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Corresponding authors.
Shangqin Chen: Department of Neonatal Paediatrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Corresponding authors.

Journal volume & issue: Vol. 273
p. 116173

Abstract

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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.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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