Department of Pesticides Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
Institute for Biochemistry, Technical University of Berlin, Straße des 17. Juni 153, 10623, Berlin, Germany.
Arch Toxicol. 2017 Aug;91(8):2895-2907. doi: 10.1007/s00204-016-1925-2. Epub 2017 Jan 6.
The agricultural fungicides cyproconazole and prochloraz exhibit hepatotoxicity in rodent studies and are tumorigenic following chronic exposure. Both substances are suspected to act via a CAR (constitutive androstane receptor)/PXR (pregnane-X-receptor)-dependent mechanism. Human relevance of these findings is under debate. A 28-day toxicity study was conducted in mice with humanized CAR and PXR (hCAR/hPXR) with two dose levels (50 or 500 ppm) of both substances, using the model CAR activator phenobarbital as a reference. Results were compared to wild-type mice. A treatment-related increase in liver weights was observed for all three substances at least at the high-dose level. Changes in the expression of classic CAR/PXR target genes such as Cyp2b10 were induced by cyproconazole and phenobarbital in both genotypes, while prochloraz treatment resulted in gene expression changes indicative of additional aryl hydrocarbon receptor activation, e.g. by up-regulation of Cyp1a1 expression. Cyproconazole-induced effects on CAR-dependent gene expression, liver weight, and hepatic lipid accumulation were more prominent in wild-type mice, where significant genotype differences were observed at the high-dose level. Moreover, high-dose cyproconazole-treated mice from the wild-type group responded with a marked increase in hepatocellular proliferation, while hCAR/hPXR mice did not. In conclusion, our data demonstrate that cyproconazole and PB induce CAR/PXR downstream effects in hepatocytes in vivo via both, the murine and human receptors. At high doses of cyproconazole, however, the responses were clearly more pronounced in wild-type mice, indicating increased sensitivity of rodents to CAR agonist-induced effects in hepatocytes.
农业杀菌剂环丙唑醇和百菌清在啮齿动物研究中具有肝毒性，并且在慢性暴露后会致癌。这两种物质都被怀疑通过 CAR（组成型雄烷受体）/PXR（孕烷 X 受体）依赖性机制发挥作用。这些发现的人类相关性仍存在争议。在具有人源化 CAR 和 PXR（hCAR/hPXR）的小鼠中进行了为期 28 天的毒性研究，使用模型 CAR 激活剂苯巴比妥作为参比物，用两种剂量水平（50 或 500 ppm）的这两种物质进行处理。将结果与野生型小鼠进行比较。至少在高剂量水平下，所有三种物质都观察到与治疗相关的肝重增加。环丙唑醇和苯巴比妥在两种基因型中均诱导 Cyp2b10 等经典 CAR/PXR 靶基因的表达发生变化，而百菌清处理导致 Cyp1a1 表达上调等表明额外的芳烃受体激活的基因表达变化。环丙唑醇诱导的 CAR 依赖性基因表达、肝重和肝内脂质积累的影响在野生型小鼠中更为明显，在高剂量水平下观察到显著的基因型差异。此外，来自野生型组的高剂量环丙唑醇处理的小鼠表现出明显的肝细胞增殖增加，而 hCAR/hPXR 小鼠则没有。总之，我们的数据表明，环丙唑醇和 PB 通过鼠和人受体在体内诱导 CAR/PXR 下游效应。然而，在高剂量的环丙唑醇下，野生型小鼠的反应明显更为明显，表明啮齿动物对 CAR 激动剂诱导的肝细胞效应的敏感性增加。
