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  3. Azole fungicides: Potential endocrine disrupting effects and impact on placental steroidogenesis via inhibiting human and rat 3β-hydroxysteroid dehydrogenase

Azole fungicides: Potential endocrine disrupting effects and impact on placental steroidogenesis via inhibiting human and rat 3β-hydroxysteroid dehydrogenase

  • Ecotoxicol Environ Saf. 2025 Jul 15:300:118471. doi: 10.1016/j.ecoenv.2025.118471.
Jingyun Yan 1,  Huan Chen 2,  Zhongyao Ji 1,  Yunbing Tang 3,  Shaowei Wang 3,  Jingyi Zheng 1,  Huitao Li 1,  Linxi Li 4,  Ren-Shan Ge 5,  Yaoyao Dong 6
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China.
  • 2 Department of Emergency, The Dingli Clinical College of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 3 Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 4 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China. Electronic address: [email protected].
  • 5 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
  • 6 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang Province 325000, China; Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China. Electronic address: [email protected].
PMID: 40472693 DOI: 10.1016/j.ecoenv.2025.118471
Abstract

Azole fungicides disrupt pregnancy, but their effects on placental 3β-hydroxysteroid dehydrogenases (3β-HSDs) and structure-activity relationships (SARs) remain unclear. This study evaluated 9 azole fungicides for their inhibitory potency, mechanism, SAR, and docking interactions with human 3β-HSD1 and rat 3β-HSD4. Bromuconazole, climbazole, cyproconazole, and etaconazole inhibited human 3β-HSD1 (IC50 = 6.21 μM to 104.83 μM), with climbazole being the most potent. These compounds acted as mixed/noncompetitive inhibitors and climbazole suppressed progesterone secretion in human JAr cells at ≥ 2.5 μM. They also inhibited rat 3β-HSD4, albeit with lower potency. Molecular docking revealed that these fungicides bind to the NAD+/steroid-binding site via hydrogen bonds, hydrophobic interactions, and van der Waals forces. A negative correlation between LogP and IC50 indicated that lipophilicity enhances inhibitory efficacy. 3D-QSAR analysis further confirmed the critical role of hydrogen bonding in binding affinity. In conclusion, climbazole exhibits the strongest inhibition of human 3β-HSD1, driven by its high lipophilicity. These findings highlight the endocrine-disrupting potential of azole fungicides and provide insights into their SAR and inhibition mechanisms, aiding risk assessment and regulatory decisions.

Keywords

3β-HSD1; Azole fungicide; Placenta; Pregnenolone; Progesterone.

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