摘要
Halogenated disinfectants are widely used in medical, household, and industrial settings, but their inhibitory effects on 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1), a key enzyme catalyzing estrone-to-estradiol (E 2 ) conversion, remain unclear. We evaluated nine compounds for inhibition of human placental and rat ovarian 17β-HSD1 using enzymatic assays, kinetic analysis, BeWo cell E 2 production assays, 3D quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics simulations (MDS), absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction, and network toxicology. Six compounds inhibited human 17β-HSD1, with half-maximal inhibitory concentration (IC 50 ) values of 0.78-14.90 μM; potency followed hexachlorophene > bithionol > bromochlorophene > fenticlor > dichlorophene > chlorophene. Rat 17β-HSD1 was inhibited by these six compounds and by triclosan, with IC 50 values of 6.13-54.77 μM. Kinetic analysis indicated mainly mixed/noncompetitive inhibition. In BeWo cells, fenticlor decreased E 2 production at ≥ 1 μM, dichlorophene at 10 and 20 μM, and bromochlorophene and hexachlorophene at 20 μM, whereas chlorophene and bithionol were inactive up to 20 μM. The 3D-QSAR model and descriptor analysis suggested associations of inhibition with hydrophobicity, aromatic features, molecular size and halogenation. Docking and 100-ns MDS supported stable binding of active compounds near the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region, particularly for hexachlorophene. Network toxicology placed HSD17B1, which encodes 17β-HSD1, within preeclampsia-related estrogen and steroidogenic pathways. These findings indicate that halogenated disinfectants may disrupt estrogen homeostasis through direct 17β-HSD1 inhibition and warrant further evaluation for reproductive and placental endocrine toxicity.
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