Halogen Atoms in Bisphenol A Derivatives Enhance the Inhibitory Potency against Human and Rat Placental 3β-Hydroxysteroid Dehydrogenases

Halogenated bisphenol A (BPA) derivatives are extensively utilized in industrial production and have been detected in the environment, as well as in human samples. The 3β-HSDs are important for the catalytic transformation of pregnenolone into progesterone. But inhibition by BPA derivatives on 3β-HSD activity is still unclear. The inhibition of 3β-HSD by 8 halogen BPA derivatives was assessed by means of an in vitro test. Tetrachloro BPA was found to be the strongest 3β-HSDs in both human and rat models with IC₅₀ values of 1.48 and 3.81 μM. Other derivatives, including 3-chloro BPA, bisphenol C, 3,3',5-trichloro BPA, tetrabromo BPA, and 4,4'-thiodiphenol, also exhibited inhibitory effects on human and rat placental 3β-HSD activity, albeit with lower potency. 3-Chloro BPA and bisphenol C exerted mixed inhibition against human 3β-HSD1, while the Others functioned as competitive inhibitors. These compounds significantly suppressed progesterone secretion in human JAr cells. The inhibitory effects were inversely correlated with the Log P (lipophilicity) and halogen atoms. Docking analysis showed hydrophobic and hydrogen bond interactions that played key roles in the inhibition mechanism. In this paper, a new pharmacological model, which includes both hydrophobic and aromatics, has been proposed for the prediction of inhibition of BPA derivatives. In summary, some halogen-containing derivatives are strong suppressors of 3β-HSDs in placenta, and the inhibition effect of these compounds is mainly dependent on the lipophilicity.