ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Chuhang Chi,Chaochao Gong,Yunbing Tang,He Zhu,Qian Zhang,Yang Zhu,Shaowei Wang,Ren-shan Ge,Xiaoheng Li
Isothiazolinone disinfectants constitute a class of broad-spectrum antimicrobial agents due to the pandemic of COVID-19. The aim of this study was to assess the impacts of six distinct isothiazolinone disinfectants on the activity of 17β-hydroxysteroid dehydrogenase 1 (17β-HSD1) in humans and rats, as well as on BeWo cells. We identified IC 50 with 4,5-dichloro-2-octyl-1,2-thiazol-3-one exhibiting the most potent inhibition (8.09 μM for human 17β-HSD1) and 5-chloro-2-methyl-1,2-thiazol-3-one showing the weak inhibition (81.94 μM for human 17β-HSD1) and these chemicals can potently inhibit estradiol production at ≥ 1 μM. Additionally, 4,5-dichloro-2-octyl-1,2-thiazol-3-one and 2-octyl-1,2-thiazol-3-one inhibited rat 17β-HSD1 at IC 50 concentrations of 20.53 and 32.47 μM, respectively. Through mode action analyses, these compounds were found to exert mixed inhibition. Computational docking simulations revealed that isothiazolinone disinfectants interact with the NADPH binding domains of the two enzymes. Bivariate correlation analysis confirmed negative relationships between physicochemical properties such as LogP and heavy atoms, and half maximum inhibition concentrations of these chemicals. 3D-QSAR analysis revealed the presence of hydrophobic and hydrogen bond regions and both positively contribute to the binding. In conclusion, isothiazolinone disinfectants repress human and rat 17β-HSD1, depending on their hydrophobicity and hydrogen bonds.
研究领域:
内分泌学
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毒理学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
2024
·
IF 2.7
Chaochao Gong,Sailing Chen,Yunbing Tang,Huiqian Chen,Jianghuan Xie,Yanning Lv,Zhefan Shen,Yang Zhu,Shaowei Wang,Ren-shan Ge,Junzhao Zhao
The objective of this study was to examine the effect of 11 organochlorine pesticides on human and rat 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) in human placental and rat ovarian microsome and on estradiol production in BeWo cells. The results showed that the IC 50 values for endosulfan, fenhexamid, chlordecone, and rhothane on human 17β-HSD1 were 21.37, 73.25, 92.80, and 117.69 μM. Kinetic analysis revealed that endosulfan acts as a competitive inhibitor, fenhexamid as a mixed/competitive inhibitor, chlordecone and rhothane as a mixed/uncompetitive inhibitor. In BeWo cells, all insecticides except endosulfan significantly decreased estradiol production at 100 μM. For rats, the IC 50 values for dimethomorph, fenhexamid, and chlordecone were 11.98, 36.92, and 109.14 μM. Dimethomorph acts as a mixed inhibitor, while fenhexamid acts as a mixed/competitive inhibitor. Docking analysis revealed that endosulfan and fenhexamid bind to the steroid-binding site of human 17β-HSD1. On the other hand, chlordecone and rhothane binds to a different site other than the steroid and NADPH-binding site. Dimethomorph binds to the steroid/NADPH binding site, and fenhexamid binds to the steroid binding site of rat 17β-HSD1. Bivariate correlation analysis showed a positive correlation between IC 50 values and LogP for human 17β-HSD1, while a slight negative correlation was observed between IC 50 values and the number of HBA. ADMET analysis provided insights into the toxicokinetics and toxicity of organochlorine pesticides. In conclusion, this study identified the inhibitory effects of 3–4 organochlorine pesticides and binding mechanisms on human and rat 17β-HSD1, as well as their impact on hormone production.
研究领域:
药理学
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毒理学
·
内分泌学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR HUMAN REPRODUCTION
·
2014
·Vol. 20
·期 8
·799-809
·
IF 3.483
Wang Yongjie,Tang Chao,Wu Minglan,Pan Yibin,Ruan Hongfeng,Chen Linling,Yao Hongyi,Zhu Haibin,Wu Ximei
We have previously demonstrated that the reduced form of vitamin C (l-ascorbic acid, AA) is able to induce the production of both steroid and peptide hormones in human choriocarcinoma cells. Here, we attempted to investigate the role and underlying mechanism of the oxidized form of vitamin C, dehydroascorbic acid (DHA), in steroidogenesis in primary human cytotrophoblasts and human choriocarcinoma cells. Messenger RNA and protein levels of steroidogenic enzymes including P450 cholesterol side-chain cleavage enzyme (P450scc), 3β-hydroxysteroid dehydrogenase type 1 (3β-HSD1), 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and aromatase were examined by quantitative RT–PCR and western blots, respectively. Progesterone (P4) and estradiol (E2) levels were determined by enzyme immunoassays. Knockdown of c-Jun was achieved by lentivirus-mediated shRNA, and signaling pathways implicated in DHA-induced steroidogenesis were examined by western blots and dual-luciferase assays. DHA dose-dependently induced the expression of steroidogenic enzymes including 3β-HSD1, 17β-HSD1 and aromatase at both mRNA and protein levels, and subsequently increased the production of E2 but not P4. These effects were synergized by diethylmaleate, a glutathione-depleting compound, and α-tocopherol, a reducing agent, but robustly attenuated by inhibition of DHA transportation by phloretin or 2-deoxy-d-glucose. DHA time-dependently inhibited JNK and c-Jun phosphorylation, and dose-dependently reduced AP1 reporter activity. JNK signaling pathway-specific inhibitor SP600125 and c-Jun shRNA both significantly increased the expression of steroidogenic enzymes and E2 production regardless of the presence or absence of DHA. These findings suggest that DHA is able to induce steroidogenesis through inhibition of JNK/c-Jun/AP1 signaling, and may therefore play indispensable roles in pregnancy maintenance.
研究领域:
内分泌学
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细胞生物学
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分子生物学
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生殖生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）