Department of Anesthesiology and Perioperative Medicine, the Second Affiliated Hospital and Yuying Children's Hospital, Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Obstetrics and Gynecology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Toxicol Appl Pharmacol. 2024 Nov;492:117133. doi: 10.1016/j.taap.2024.117133. Epub 2024 Oct 23.
This study delved into the impacts of 10 parabens on the activity of human and rat gonadal 3β-hydroxysteroid dehydrogenase (3β-HSD) within human KGN cell and rat testicular microsomes, as well as on the secretion of progesterone in KGN cells and the inhibitory potency was compared between human and rats. Intriguingly, the outcomes revealed that ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl parabens displayed varying IC values for human 3β-HSD2, from 4.15 to 139.96 μM, demonstrating characteristics of mixed inhibitors. Notably, within KGN cells, all examined parabens, excluding nonyl and phenyl parabens, significantly inhibited progesterone secretion at 5-50 μM. In the case of rats, the IC values for these parabens on gonadal 3β-HSD1 fluctuated between 7.15 and 110.76 μM, likewise functioning as mixed inhibitors. Through docking analysis, it was proposed that most parabens effectively bind to NAD and/or steroid binding site. Moreover, bivariate correlation analysis unveiled an inverse correlation between IC values and structural characteristics such as LogP, molecular weight, heavy atom number, and carbon number within the alcohol moiety of parabens. 3D-QSAR elucidated pivotal regions, comprising hydrogen bond donor, hydrogen bond acceptor, and hydrophobic region, with the most potent inhibitor nonyl paraben engaging with all regions, while the weakest inhibitor ethyl paraben interacted with the regions except for the hydrophobic region. In conclusion, this investigation underscored the inhibitory effects imparted by several parabens on both human and rat gonadal 3β-HSD activity, with their inhibitory potency being modulated by aspects of hydrophobicity and carbon chain length.
本研究深入探讨了 10 种对羟基苯甲酸酯对人源和鼠源卵巢 3β-羟甾脱氢酶（3β-HSD）在人源 KGN 细胞和鼠睾丸微粒体中的活性、KGN 细胞中孕酮分泌的影响，并比较了人源和鼠源 3β-HSD 的抑制效力。结果表明，乙基、丙基、丁基、己基、庚基、壬基、苯基和苄基对羟基苯甲酸酯对人源 3β-HSD2 的抑制作用的 IC50 值范围为 4.15-139.96 μM，表现为混合抑制剂的特征。值得注意的是，在所检测的对羟基苯甲酸酯中，除壬基和苯基对羟基苯甲酸酯外，其余对羟基苯甲酸酯在 5-50 μM 浓度下均显著抑制 KGN 细胞中孕酮的分泌。在鼠源中，这些对羟基苯甲酸酯对性腺 3β-HSD1 的 IC50 值在 7.15-110.76 μM 之间波动，同样作为混合抑制剂。通过对接分析，提出大多数对羟基苯甲酸酯能有效地与 NAD 和/或甾体结合位点结合。此外，双变量相关分析揭示了对羟基苯甲酸酯的 IC 值与结构特征（如 LogP、分子量、重原子数和醇部分的碳原子数）之间存在负相关关系。3D-QSAR 揭示了关键区域，包括氢键供体、氢键受体和疏水区，最有效的抑制剂壬基对羟基苯甲酸酯与所有区域结合，而最弱的抑制剂乙基对羟基苯甲酸酯与除疏水区以外的区域结合。总之，本研究强调了几种对羟基苯甲酸酯对人源和鼠源性腺 3β-HSD 活性的抑制作用，其抑制效力受疏水性和碳链长度等因素的调节。
