Hepato-Gastroenterology, Chiayi Christian Hospital, Chiayi 600, Taiwan, ROC.
Toxicology. 2013 Feb 8;304:32-40. doi: 10.1016/j.tox.2012.11.018. Epub 2012 Dec 7.
Cyprodinil is a pyrimidinamine fungicide, used worldwide by agriculture. It is used to protect fruit plants and vegetables from a wide range of pathogens. Benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are toxic environmental pollutants and are prototypes of aryl hydrocarbon receptor (AHR) ligands. Although the structure of cyprodinil distinctly differs from those of BaP and TCDD, our results show that cyprodinil induced nuclear translocation of the AHR, and induced the transcriptional activity of aryl hydrocarbon response element (AHRE). Cyprodinil induced the expression of cytochrome P450 (CYP) 1A1, a well-known AHR-targeted gene, in ovarian granulosa cells, HO23, and hepatoma cells, Hepa-1c1c7. Its induction did not appear in AHR signal-deficient cells, and was blocked by the AHR antagonist, CH-223191. Cyprodinil decreased AHR expression in HO23 cells, resulting in CYP1A1 expression decreasing after it peaked at 9h of treatment in HO23 cells. Dexamethasone is a synthetic agonist of glucocorticoids. Cyprodinil enhanced dexamethasone-induced gene expression, and conversely, its induction of CYP1A1 expression was decreased by dexamethasone in HO23 cells, indicating its induction of crosstalk between the AHR and glucocorticoid receptor and its role as a potential endocrine disrupter. In addition to BaP, TCDD, and an AHR agonist, β-NF, cyprodinil also phosphorylated extracellular signal-regulated kinase (ERK) in HO23 and Hepa-1c1c7 cells, indicating its deregulation of ERK activity. In summary, our results demonstrate that cyprodinil, similar to BaP, acts as an AHR activator, a potential endocrine disrupter, and an ERK disrupter.
环丙嘧啶是一种嘧啶胺类杀菌剂，在世界范围内被农业广泛使用。它用于保护水果植物和蔬菜免受多种病原体的侵害。苯并[a]芘（BaP）和 2,3,7,8-四氯二苯并对二恶英（TCDD）是有毒的环境污染物，也是芳烃受体（AHR）配体的原型。尽管环丙嘧啶的结构明显不同于 BaP 和 TCDD，但我们的结果表明，环丙嘧啶诱导 AHR 的核转位，并诱导芳烃反应元件（AHRE）的转录活性。环丙嘧啶诱导卵巢颗粒细胞、HO23 和肝癌细胞 Hepa-1c1c7 中细胞色素 P450（CYP）1A1 的表达，这是一种众所周知的 AHR 靶向基因。其诱导作用在 AHR 信号缺陷细胞中不出现，并被 AHR 拮抗剂 CH-223191 阻断。环丙嘧啶降低 HO23 细胞中的 AHR 表达，导致 CYP1A1 表达在处理 9 小时后达到峰值后下降。地塞米松是一种合成的糖皮质激素激动剂。环丙嘧啶增强地塞米松诱导的基因表达，相反，地塞米松降低了 HO23 细胞中环丙嘧啶诱导的 CYP1A1 表达，表明其诱导 AHR 和糖皮质激素受体之间的串扰及其作为潜在内分泌干扰物的作用。除了 BaP、TCDD 和 AHR 激动剂 β-NF 外，环丙嘧啶还在 HO23 和 Hepa-1c1c7 细胞中磷酸化细胞外信号调节激酶（ERK），表明其对 ERK 活性的失调。总之，我们的结果表明，环丙嘧啶与 BaP 类似，作为 AHR 激活剂、潜在的内分泌干扰物和 ERK 干扰物发挥作用。
