Per- and polyfluoroalkyl substances inhibit human and rat 17ß-hydroxysteroid dehydrogenase 1: Quantitative structure-activity relationship and molecular docking analysis.
Ecotoxicol Environ Saf
; 273: 116173, 2024 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-38452703
ABSTRACT
Per- and polyfluoroalkyl (PFAS) substances are enduring industrial materials. 17ß-Hydroxysteroid dehydrogenase isoform 1 (17ß-HSD1) is an estrogen metabolizing enzyme, which transforms estrone into estradiol in human placenta and rat ovary. Whether PFAS inhibit 17ß-HSD1 and what the structure-activity relationship (SAR) remains unexplored. We screened 18 PFAS for inhibiting human and rat 17ß-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⯵M substantially inhibited human 17ß-HSD1, with order of C11 (half-maximal inhibition concentration, IC50, 8.94⯵M) > C10 (10.52⯵M) > C12 (14.90⯵M) > C13 (30.97⯵M) > C9 (43.20⯵M) > C14 (44.83⯵M) > C8 (73.38⯵M) > others. Of the 7 per- and poly-fluorosulfonic acids (PFSAs), the potency was C8S (IC50, 14.93⯵M) > C7S (80.70⯵M) > C6S (177.80⯵M) > others. Of the PFCAs, C8-C14 PFCAs at 100⯵M markedly reduced rat 17ß-HSD1 activity, with order of C11 (IC50, 9.11⯵M) > C12 (14.30⯵M) > C10 (18.24⯵M) > C13 (25.61⯵M) > C9 (67.96⯵M) > C8 (204.39⯵M) > others. Of the PFSAs, the potency was C8S (IC50, 37.19⯵M) > C7S (49.38⯵M) > others. In contrast to PFOS (C6S), the partially fluorinated compound 62 FTS with an equivalent number of carbon atoms demonstrated no inhibition of human and rat 17ß-HSD1 activity at a concentration of 100⯵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 17ß-HSD1 was more sensitive than rat enzyme. PFAS inhibited human and rat 17ß-HSD1 in a mixed mode. Docking analysis revealed that they bind to the NADPH and steroid binding site of both 17ß-HSD1 enzymes. The 3D quantitative SAR (3D-QSAR) showed that hydrophobic region, hydrogen bond acceptor and donor are key factors in binding to 17ß-HSD1 active sites. In conclusion, PFAS exhibit inhibitory effects on human and rat 17ß-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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Relação Quantitativa Estrutura-Atividade
/
Fluorocarbonos
Limite:
Animals
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Female
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Humans
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Pregnancy
Idioma:
En
Revista:
Ecotoxicol Environ Saf
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China