Comparison of structure-activity relationship for bisphenol analogs in the inhibition of gonadal 3β-hydroxysteroid dehydrogenases among human, rat, and mouse

Ya Chen; Huina Zhang; Yang Yu; Shaowei Wang; Mengyun Wang; Chengshuang Pan; Qianjin Fei; Huitao Li; Yiyan Wang; Jieqiang Lv; Ren-Shan Ge

doi:10.1016/j.jsbmb.2023.106424

Comparison of structure-activity relationship for bisphenol analogs in the inhibition of gonadal 3β-hydroxysteroid dehydrogenases among human, rat, and mouse

J Steroid Biochem Mol Biol. 2024 Feb:236:106424. doi: 10.1016/j.jsbmb.2023.106424. Epub 2023 Nov 7.

Authors

Ya Chen¹, Huina Zhang², Yang Yu³, Shaowei Wang², Mengyun Wang², Chengshuang Pan⁴, Qianjin Fei⁵, Huitao Li², Yiyan Wang⁶, Jieqiang Lv⁷, Ren-Shan Ge⁸

Affiliations

¹ Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Reproductive Medicine Center, 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, Zhejiang 325000, China.
² Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
³ Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou, Zhejiang 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, and Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325000, China.
⁴ Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Reproductive Medicine Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁵ Reproductive Medicine Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
⁶ Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou, Zhejiang 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, and Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325000, China.
⁷ Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: jieqianglu@126.com.
⁸ Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou, Zhejiang 325027, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, and Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, Zhejiang 325000, China. Electronic address: renshan_ge@wmu.edu.

PMID: 37939739
DOI: 10.1016/j.jsbmb.2023.106424

Abstract

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.

Keywords: 3β-hydroxysteroid dehydrogenase; Bisphenols; Docking analysis; Lipophilicity; Progesterone.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

17-Hydroxysteroid Dehydrogenases / metabolism
3-Hydroxysteroid Dehydrogenases / metabolism
Animals
Benzhydryl Compounds*
Humans
Hydroxysteroid Dehydrogenases* / metabolism
Male
Mice
Molecular Docking Simulation
Phenols*
Rats
Structure-Activity Relationship
Testis* / metabolism

Substances

bisphenol A
Hydroxysteroid Dehydrogenases
3-Hydroxysteroid Dehydrogenases
17-Hydroxysteroid Dehydrogenases
Benzhydryl Compounds
Phenols