Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition
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-hydroxyst...
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Elsevier
2025-06-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325005627 |
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| author | Ke Zheng Shufang Qi Fangzheng Shan Rong Cui Shaowei Wang Wanyu Li Jin Yang Ren-shan Ge Yiyan Wang |
| author_facet | Ke Zheng Shufang Qi Fangzheng Shan Rong Cui Shaowei Wang Wanyu Li Jin Yang Ren-shan Ge Yiyan Wang |
| author_sort | Ke Zheng |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-92da750f1bc04f7da438352e2d553525 |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-92da750f1bc04f7da438352e2d5535252025-08-20T03:53:12ZengElsevierEcotoxicology and Environmental Safety0147-65132025-06-0129711822610.1016/j.ecoenv.2025.118226Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibitionKe Zheng0Shufang Qi1Fangzheng Shan2Rong Cui3Shaowei Wang4Wanyu Li5Jin Yang6Ren-shan Ge7Yiyan Wang8Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, ChinaDepartment 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; Corresponding authors at: Department of Anesthesiology and Perioperative Medicine, 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 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; Corresponding authors at: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.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.http://www.sciencedirect.com/science/article/pii/S0147651325005627Isothiazolinone biocides3β-Hydroxysteroid dehydrogenaseMode of actionDocking analysis3D-QSAR |
| spellingShingle | Ke Zheng Shufang Qi Fangzheng Shan Rong Cui Shaowei Wang Wanyu Li Jin Yang Ren-shan Ge Yiyan Wang Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition Ecotoxicology and Environmental Safety Isothiazolinone biocides 3β-Hydroxysteroid dehydrogenase Mode of action Docking analysis 3D-QSAR |
| title | Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition |
| title_full | Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition |
| title_fullStr | Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition |
| title_full_unstemmed | Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition |
| title_short | Impact of isothiazolinone biocides on gonadal steroid production: Focus on 3β-hydroxysteroid dehydrogenase inhibition |
| title_sort | impact of isothiazolinone biocides on gonadal steroid production focus on 3β hydroxysteroid dehydrogenase inhibition |
| topic | Isothiazolinone biocides 3β-Hydroxysteroid dehydrogenase Mode of action Docking analysis 3D-QSAR |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325005627 |
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