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.