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Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Chain-length matters: How benzylalkyldimethylammonium quaternary disinfectants disrupt gonadal steroidogenesis via
Mengyao Yin1, Jingyun Yan2, Cong Chen2
1Reproductive Centre, Department of Obstetrics and Gynecology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Abstract:
Benzylalkyldimethylammonium (BAC) quaternary disinfectants are extensively used as antimicrobial agents. However, the specific BACs responsible for inhibition and their structure-activity relationship (SAR) for human 3β-hydroxysteroid dehydrogenase 2 (3β-HSD2) and its homolog rat 3β-HSD1, the critical enzyme in gonadal steroidogenesis, remain poorly understood. This study evaluated nine BACs for their inhibitory effects on human 3β-HSD2 and rat 3β-HSD1, determining potency (IC50), inhibition kinetics, cellular impact, and binding interactions via molecular docking and 3D-QSAR. Inhibitory potency (IC50) revealed C18 (11.84 μM) > C16 (15.51 μM) > C14 (25.25 μM) > C12 (30.63 μM) > C10 (56.86 μM) > C1-C8 BACs (no inhibition at 100 μM) against human 3β-HSD2 and C18 (8.23 μM) > C16 (10.74 μM) > C14 (12.21 μM) > C12 (14.38 μM) > C10 (26.62 μM) > C1-C8 BACs (no inhibition at 100 μM) against rat 3β-HSD1. Both enzymes exhibited mixed-type inhibition. Cellular suppression showed that C14, C16, and C18 BACs inhibited progesterone synthesis in human KGN granulosa tumor cells at ≥ 5 μM. Docking and SAR revealed binding at the NAD+ /steroid site via hydrogen bonding, hydrophobic, and van der Waals interactions. Lipophilicity (LogP), steric bulk, Fsp3, and flexibility correlated positively with potency, indicating that longer alkyl chains (≤C18) enhance inhibition. 3D-QSAR confirmed the importance of hydrophobic regions in binding affinity due to long alkyl chain. In conclusion, BACs inhibit gonadal 3β-HSD activity in a chain-length-dependent manner (C10-C18), with lipophilicity as a key determinant. These findings suggest that BAC disinfectants may act as potential endocrine disruptors by interfering with steroidogenesis.
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