Comparison of structure-activity relationship for bisphenol analogs in the inhibition of gonadal 3β-hydroxysteroid dehydrogenases among human, rat, and mouse.

Bisphenol A (BPA) is a widely used plastic material and its potential endocrine disrupting effect has restricted its use and increasing use of BPA alternatives has raised health concerns. However, the effect of bisphenol alternatives on steroidogenesis remains unclear. The objective of this study was to compare inhibitory potencies of 10 BPA alternatives in the inhibition of gonadal 3β-hydroxysteroid dehydrogenase (3β-HSD) in three species (human, rat and mouse). The inhibitory potency for human 3β-HSD2, rat 3β-HSD1, and mouse 3β-HSD6 ranged from bisphenol FL (IC50, 3.32 μM for human, 5.19 μM for rat, and 3.26 μM for mouse) to bisphenol E, F, and thiodiphenol (ineffective at 100 μM). Most BPA alternatives were mixed inhibitors of gonadal 3β-HSD and they dose-dependently inhibited progesterone formation in KGN cells. Molecular docking analysis showed that all BPA analogs bind to steroid and NAD+ active sites. Lipophilicity of BPA alternatives was inversely correlated with IC50 values. In conclusion, BPA alternatives mostly can inhibit gonadal 3β-HSDs and lipophilicity determines their inhibitory strength.

Chen Y ，Zhang H ，Yu Y ，Wang S ，Wang M ，Pan C ，Fei Q ，Li H ，Wang Y ，Lv J ，Ge RS ... -  《-》

Benzene ring bisphenol A substitutes potently inhibit human, rat, and mouse gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a chemical used in the production of certain plastics and resins. Recent research has found that BPA can inhibit the activity of 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3β-HSDs). Whether benzene ring BPA substitutes can inhibit human, rat, and mouse gonadal 3β-HSDs, the structure-activity relationship and the underlying mechanism remain unclear. In this study, we compared 6 benzene ring BPA substitutes to BPA in the inhibition of human, rat, and mouse gonadal 3β-HSDs and conducted structure-activity relationship and in silico docking analysis. The inhibitory activity (IC50) of human 3β-HSD2 in KGN cells ranged from about 0.02 μM for bisphenol H to 8.75 μM for BPA, that of rat 3β-HSD1 in testicular microsomes ranged from 0.099 μM for bisphenol H to 31.32 μM for BPA, and that of mouse 3β-HSD6 ranged from 0.021 μM for BPH to ineffectiveness for 100 μM BPA. These compounds acted as mixed inhibitors with LogP inversely correlated with IC50 and ΔG positively correlated with IC50 value. Docking analysis showed that these compounds bind to the steroid active site of the 3β-HSD enzymes. In conclusion, some benzene ring BPA substitutes potently inhibit gonadal 3β-HSD in various species, and lipophilicity and binding affinity determine their inhibitory strength.

Yu Y ，Ren Z ，Wang H ，Sang J ，Chen Y ，Zhang M ，Zhu Y ，Wang Y ，Ge RS ... -  《-》

Benzophenone-1 and -2 UV-filters potently inhibit human, rat, and mouse gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Benzophenone (BP) ultraviolet (UV) -filters have been widely used to prevent adverse effects of UV. Whether they can disrupt gonadal steroidogenesis remains unclear. Gonadal 3β-hydroxysteroid dehydrogenases (3β-HSD) catalyse the conversion of pregnenolone to progesterone. This study explored the effect of 12 BPs on human, rat, and mouse 3β-HSD isoforms, and analysed the structure-activity relationship (SAR) and underlying mechanisms. The inhibitory potency was BP-1 (IC50, 5.66 ± 0.95 μM) > BP-2 (5.84 ± 2.22 μM) > BP-6 (185.8 ± 115.2 μM) > BP3-BP12 on human KGN 3β-HSD2, BP-2 (5.90 ± 1.02 μM) > BP-1 (7.55 ± 1.26 μM) > BP3-B12 on rat testicular 3β-HSD1, and BP-1 (15.04 ± 5.20 μM) > BP-2 (22.64 ± 11.81 μM) > BP-6（125.1 ± 34.65 μM）> BP-7 (161.1 ± 102.4 μM) > other BPs on mouse testicular 3β-HSD6. BP-1 is a mixed inhibitor of human, rat, and mouse 3β-HSDs, and BP-2 is a mixed inhibitor of human and rat 3β-HSDs and a noncompetitive inhibitor of mouse 3β-HSD6. 4-Hydroxyl substitution in the benzene ring plays a key role in enhancing potency of inhibiting human, rat, and mouse gonadal 3β-HSDs. BP-1 and BP-2 can penetrate human KGN cells to inhibit progesterone secretion at ≥ 10 μM. Docking analysis revealed that the 4-hydroxyl group of BP-1 and BP-2 forms hydrogen bonds with residue Ser123 of human 3β-HSD2 and residue Asp127 of rat 3β-HSD1. In conclusion, this study demonstrates that BP-1 and BP-2 are the most potent inhibitors of human, rat, and mouse gonadal 3β-HSDs and that there is a significant SAR difference.

Wang M ，Yu Y ，Tang Y ，Pan C ，Fei Q ，Hu Z ，Li H ，Zhu Y ，Wang Y ，Ge RS ... -  《-》

Inhibition of human and rat placental 3β-hydroxysteroid dehydrogenases by bisphenol A analogues depends on their hydrophobicity: In silico docking analysis.

Wang S ，Lu H ，Zhai Y ，Tang Y ，Su M ，Li H ，Wang Y ，Liu Y ，Ge RS ... -  《-》

Halogenated bisphenol A derivatives potently inhibit human, rat, and mouse gonadal 3β-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico molecular docking analysis.

Bisphenol A (BPA) is a widely used plastic material, and halogenated BPA derivatives are formed either by synthesis or environmental processes. However, the effect of halogenated bisphenols on steroidogenesis remains unclear. The aim of this study was to compare inhibition of 6 BPA derivatives on gonadal 3β-hydroxysteroid dehydrogenases (3β-HSDs) in three species (human, rat, and mouse). The inhibition on human 3β-HSD2 was tetrabromo BPA (TBBPA, IC50, 1.01 μM)>trichloro BPA (TrCBPA, 3.95 μM)>tetrachloro BPA (TCBPA, 4.14 μM)>monochloro BPA (MCBPA, 4.74 μM)>others with TrCBPA of competitive, TBBPA of noncompetitive and MCBPA/TCBPA of mixed inhibition. The inhibition on rat 3β-HSD1 was TCBPA (1.68 μM)>TrCBPA (1.72 μM)>MCBPA (2.80 μM)>BPA>others with mixed inhibition. The inhibition on mouse 3β-HSD6 was TrCBPA (1.59 μM) >MCBPA (3.36 μM)>TCBPA (3.72 μM)>others with mixed inhibition. Molecular docking analysis showed that TBBPA, TrCBPA, and TCBPA bind to steroid active sites, contacting with catalytic residue Tyr154 of human 3β-HSD2. MCBPA, TrCBPA, and TCBPA bind to steroid active site of rat 3β-HSD1. MCBPA and TrCBPA bind to active site of mouse 3β-HSD6. Regression of lowest binding energy values with Ki values revealed a significant negative linear regression (P < 0.05). In conclusion, halogenated BPA derivatives are more potent inhibitors of three 3β-HSDs than BPA and there is structure-dependent inhibition. SYNOPSIS: Chlorinated bisphenol derivatives after water chlorination process and other halogenated bisphenols effectively inhibit human and rat 3β-HSD activity, thereby leading to steroid hormone deficiency.

Yu Y ，Wang M ，Chen Y ，Pan C ，Fei Q ，Zhu Y ，Li H ，Ge RS ... -  《-》