Halogen atoms determine the inhibitory potency of halogenated bisphenol A derivatives on human and rat placental 11ß-hydroxysteroid dehydrogenase 2.

ABSTRACT

Some halogenated bisphenol A (BPA) derivatives (tetrabromobisphenol A, TBBPA, and tetrachlorobisphenol A, TCBPA) are produced in a high volume and exist in PM2.5 after waste burning. 11ß-Hydroxysteroid dehydrogenase 2 (11ß-HSD2) is a critical enzyme for placental function. However, whether halogenated bisphenols inhibit 11ß-HSD2 and the mode of action remains unclear. The objective of this study was to investigate BPA derivatives on human and rat placental 11ß-HSD2. The inhibitory strength on human 11ß-HSD2 was TBBPA (IC50, 0.665 µM)>TCBPA (2.22 µM)>trichloro BPA (TrCBPA, 19.87 µM)>tetrabromobisphenol S (TBBPS, 36.76 µM)>monochloro BPA (MCBPA, 104.0 µM)>BPA (144.9 µM)>bisphenol S. All chemicals are mixed and competitive inhibitors. Rat 11ß-HSD2 was less sensitive to BPA derivatives, with TBBPA (IC50, 96.63 µM)>TCBPA (99.69 µM)>TrCBPA (104.1 µM)>BPA (117.1 µM)>others. Docking analysis showed that BPA derivatives bind steroid active sites. Structure-activity relationship revealed that halogen atoms and LogP were inversely correlated with inhibitory strength on human 11ß-HSD2, while LogS and polar desolvation energy were positively correlated with the inhibitory strength. In conclusion, halogenated BPA derivatives are mostly potent inhibitors on human 11ß-HSD2 and there is structure-dependent inhibition.