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  3. Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition

Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition

  • Ecotoxicol Environ Saf. 2025 Jun 1:297:118226. doi: 10.1016/j.ecoenv.2025.118226.
Ke Zheng 1,  Shufang Qi 1,  Fangzheng Shan 1,  Rong Cui 1,  Shaowei Wang 1,  Wanyu Li 1,  Jin Yang 1,  Ren-Shan Ge 2,  Yiyan Wang 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
  • 2 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China. Electronic address: renshan_ge@wmu.edu.cn.
  • 3 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Precision Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, Wenzhou, Zhejiang 325027, China. Electronic address: yywang0119@wmu.edu.cn.
PMID: 40286734 DOI: 10.1016/j.ecoenv.2025.118226
Abstract

Isothiazolinone biocides have been widely used as disinfectants during the COVID-19 pandemic. However, their effects on gonadal steroidogenesis remain unclear. This study investigated the endocrine-disrupting potential of isothiazolinone biocides, focusing on their inhibition of gonadal 3β-hydroxysteroid dehydrogenases (3β-HSDs). Enzymatic assays, molecular docking, and 3D-QSAR analyses evaluated the impact of seven isothiazolinones on human KGN cell 3β-HSD2 (h3β-HSD2) and rat testicular 3β-HSD1 (r3β-HSD1). Dichlorooctylisothiazolinone, butylbenzo[d]isothiazol-3(2 H)-one, octylisothiazolinone, and benzisothiazolinone inhibited h3β-HSD2 with IC50 values of 4.02, 15.35, 12.12, and 30.55 μM, respectively. These compounds also inhibited r3β-HSD1 with IC50 values of 1.67, 16.51, 13.25, and 29.28 μM, respectively. Whereas, methylchloroisothiazolinone selectively inhibited r3β-HSD1 with IC50 value of 40.11 μM. The compounds acted as mixed/noncompetitive inhibitors, targeting the NAD+ binding pocket. Inhibitory potency correlated with compound hydrophobicity, heavy atom count, and molecular weight. A 3D-QSAR pharmacophore model achieved high predictive accuracy (R2 = 0.98) for h3β-HSD2 inhibition. These biocides suppressed progesterone production in human KGN granulosa tumor cells. The binding free energies were ranged from -6.52 to -7.19 kcal/mol for h3β-HSD2 and -6.0 to -7.04 kcal/mol for r3β-HSD1. The results underscore the endocrine-disrupting capabilities of isothiazolinones via inhibition of critical steroidogenic Enzymes, offering insights into their structure-activity relationships and potential side effects.

Keywords

3D-QSAR; 3β-Hydroxysteroid dehydrogenase; Docking analysis; Isothiazolinone biocides; Mode of action.

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