German Federal Institute for Risk Assessment, Dept. Food Safety, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
German Federal Institute for Risk Assessment, Dept. Pesticides Safety, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Food Chem Toxicol. 2019 Jan;123:481-491. doi: 10.1016/j.fct.2018.11.039. Epub 2018 Nov 17.
Tebuconazole, a member of the triazole group of fungicides, exerts hepatotoxicity in rodent studies. Knowledge on the molecular mechanisms underlying tebuconazole toxicity is limited. Previous studies suggest that activation of xenobiotic-sensing nuclear receptors plays a role in triazole fungicide-mediated hepatotoxicity. This study aimed to characterize the ability of tebuconazole to activate gene expression via the aryl hydrocarbon receptor (AHR). Results demonstrate a statistically significant induction of the AHR target genes CYP1A1 and CYP1A2 in HepG2 and HepaRG human liver cells in vitro at concentrations corresponding to tebuconazole tissue levels reached under subtoxic conditions in vivo. CYP1A1 and CYP1A2 induction was abolished in the presence of an AHR antagonist or in AHR-knockout HepaRG cells, substantiating the importance of the AHR for the observed effects. Although the results indicate that tebuconazole is a weak inducer of AHR-dependent genes, combined exposure of HepaRG cells to tebuconazole and the previously identified AHR agonist propiconazole showed additive effects on CYP1A1 and CYP1A2 expression. In summary, we demonstrate that AHR-downstream gene expression is affected by tebuconazole in an AHR-dependent manner. Data indicate that dose addition may be assumed for the assessment of AHR-related effects of triazole fungicide mixtures.
戊唑醇是一种三唑类杀菌剂，在啮齿动物研究中具有肝毒性。目前对于戊唑醇毒性的分子机制知之甚少。先前的研究表明，外源物质感应核受体的激活在三唑类杀菌剂介导的肝毒性中发挥作用。本研究旨在探讨戊唑醇是否通过芳香烃受体（AHR）激活基因表达。结果表明，在体外实验中，戊唑醇在浓度相当于体内亚毒性条件下达到的组织水平时，可显著诱导 HepG2 和 HepaRG 人肝细胞中 AHR 靶基因 CYP1A1 和 CYP1A2 的表达。在存在 AHR 拮抗剂或 AHR 基因敲除 HepaRG 细胞的情况下，CYP1A1 和 CYP1A2 的诱导作用被消除，这证明了 AHR 对于观察到的效应非常重要。虽然结果表明戊唑醇是一种弱诱导 AHR 依赖性基因的物质，但 HepaRG 细胞联合暴露于先前鉴定的 AHR 激动剂丙环唑和戊唑醇显示对 CYP1A1 和 CYP1A2 表达具有相加作用。综上所述，本研究证明 AHR 下游基因表达受戊唑醇以 AHR 依赖的方式影响。数据表明，在评估三唑类杀菌剂混合物的 AHR 相关效应时，可以假设剂量相加。
