title: Cyprodinil as an activator of aryl hydrocarbon receptor.
abstract: 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.
authors.affiliation: Hepato-Gastroenterology, Chiayi Christian Hospital, Chiayi 600, Taiwan, ROC.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Fang
authors.forename: Fei-Yun
authors.initials: FY
authors.lastname: Chen
authors.forename: Chang-Rong
authors.initials: CR
authors.lastname: Chen
authors.forename: Chien-Chiang
authors.initials: CC
authors.lastname: Liu
authors.forename: Liang-Chi
authors.initials: LC
authors.lastname: Wong
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liu
authors.forename: Jyan-Gwo Joseph
authors.initials: JG
authors.lastname: Su
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D021381:Protein Transport / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000633:toxicity*; D020239:Receptor Cross-Talk / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects* / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D013997:Time Factors
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D000072317:Polychlorinated Dibenzodioxins; D011720:Pyrazoles; D011743:Pyrimidines; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; C108338:cyprodinil; D003907:Dexamethasone; D019363:Cytochrome P-450 CYP1A1; D048049:Extracellular Signal-Regulated MAP Kinases