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

Yang Yu; Mengyun Wang; Ya Chen; Chengshuang Pan; Qianjin Fei; Yang Zhu; Huitao Li; Ren-Shan Ge

doi:10.1016/j.toxlet.2023.09.002

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

Toxicol Lett. 2023 Sep 1:386:20-29. doi: 10.1016/j.toxlet.2023.09.002. Epub 2023 Sep 7.

Authors

Yang Yu¹, Mengyun Wang², Ya Chen³, Chengshuang Pan³, Qianjin Fei⁴, Yang Zhu², Huitao Li⁵, Ren-Shan Ge⁶

Affiliations

¹ Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital；Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, and Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325000 Zhejiang Province, China.
² Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital；Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, China.
³ Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital；Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, China; Reproductive Medicine Centre, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁴ Reproductive Medicine Centre, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital；Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, China. Electronic address: lihuitao@wmu.edu.cn.
⁶ Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, China; Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital；Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, China; Reproductive Medicine Centre, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, and Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou 325000 Zhejiang Province, China. Electronic address: renshan_ge@wmu.edu.cn.

PMID: 37683804
DOI: 10.1016/j.toxlet.2023.09.002

Abstract

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.

Keywords: 3β-hydroxysteroid dehydrogenase; Mode of action; Pregnenolone; Progesterone; Steroid hormones.