Halogen atoms determine the inhibitory potency of halogenated bisphenol A derivatives on human and rat placental 11β-hydroxysteroid dehydrogenase 2. (May 2023)

• Record Type: Journal Article
• Authors: Shi, Lei; Zhang, Bingru; Ying, Yingfen; Tang, Yunbing; Wang, Shaowei; Zhu, Yang; Li, Huitao; Ge, Ren-shan; Liu, Yi
• Is Part Of: Food and chemical toxicology. Volume 175(2023)
• Publication Date: 2023-05
• Subjects: Bisphenol A -- Halogenated bisphenol derivatives -- 11β-HSD2 -- Cortisol -- Structure-activity relationship -- Mode of action; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2023.113739
• Languages: English
• ISSNs: 0278-6915

Abstract

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. 11β-Hydroxysteroid dehydrogenase 2 (11β-HSD2) is a critical enzyme for placental function. However, whether halogenated bisphenols inhibit 11β-HSD2 and the mode of action remains unclear. The objective of this study was to investigate BPA derivatives on human and rat placental 11β-HSD2. The inhibitory strength on human 11β-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 11β-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 11β-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 11β-HSD2 and there is structure-dependent inhibition. Graphical abstract: Image 1 Highlights: Halogenated BPA derivatives potently inhibit human and rat 11β-HSD2. TBBPA is the most potent inhibitor of human 11β-HSD2. Rat 11β-HSD2 is less sensitive than human enzyme to halogenated BPA derivatives. Halogen atoms, solubility, hydrophobicity determines the inhibitory potency. Abstract : Halogenated bisphenol A derivatives inhibit human 11β-HSD2 activity, thereby leading to placental dysfunction and fetal growth retardation.