Zearalenone-Induced Interaction between PXR and Sp1 Increases Binding of Sp1 to a Promoter Site of the eNOS, Decreasing Its Transcription and NO Production in BAECs

Abstract

Zearalenone (ZEN) is a non-steroidal mycotoxin that has various toxicological impacts on mammalian health. Here, we found that ZEN significantly affected the production of nitric oxide (NO) and the expression of endothelial NO synthase (eNOS) of bovine aortic endothelial cells (BAECs). A promoter analysis using 5′-serially deleted human eNOS promoter revealed that the proximal region (−135 to +22) was responsible for ZEN-mediated reduction of the human eNOS promoter activity. This effect was reversed by mutation of two specificity protein 1 (Sp1) binding elements in the human eNOS promoter. A chromatin immunoprecipitation assay revealed that ZEN increased Sp1 binding to the bovine eNOS promoter region (−113 to −12), which is homologous to −135 to +22 of the human eNOS promoter region. We also found that ZEN promoted the binding of the pregnane X receptor (PXR) to Sp1 of the bovine eNOS, consequently decreasing eNOS expression. This reduction of eNOS could have contributed to the decreased acetylcholine-induced vessel relaxation upon ZEN treatment in our ex vivo study using mouse aortas. In conclusion, our data demonstrate that ZEN decreases eNOS expression by enhancing the binding of PXR-Sp1 to the eNOS promoter, thereby decreasing NO production and potentially causing vessel dysfunction.

Concentration of Zearalenone, Alpha-Zearalenol and Beta-Zearalenol in the Myocardium and the Results of Isometric Analyses of the Coronary Artery in Prepubertal Gilts

“…Zearalenone is also characterized by a nonmonotonic dose-response curve (according to the principle of hormesis [43]). Therefore, the results of research studies investigating the effects of different ZEN doses on tissues [44,45], cells [46] and cell organelles [47] are difficult to compare.…”

Mycotoxin Zearalenone Attenuates Innate Immune Responses and Suppresses NLRP3 Inflammasome Activation in LPS-Activated Macrophages

“…During infection, activated macrophages secrete proinflammatory cytokines (e.g., TNF-α, IL-1β and IL-6) and inflammatory mediators (e.g., NO and PGE 2 ) to regulate inflammatory responses against pathogens. A previous study showed that ZEA decreases the iNOS expression and NO production by bovine aortic endothelial cells, resulting in vessel dysfunction [ 29 ]. Marin et al also pointed out that ZEA reveals antagonistic effects on inflammation by decreasing IL-1β and TNF-α expressions in a human hepatocellular carcinoma cell line, HepG2 [ 30 ]; additionally, daily intake of ZEA also decreases the serum level of TNF-α in mice [ 31 ].…”

Kaempferol Inhibits Zearalenone-Induced Oxidative Stress and Apoptosis via the PI3K/Akt-Mediated Nrf2 Signaling Pathway: In Vitro and In Vivo Studies

“…Zearalenone (ZEA) is an oestrogenic mycotoxin responsible for polluting cereal grains, for instance oats, barley or sorghum across the globe. Many studies have shown that ZEA and its metabolites may be ingested and lead to various harmful effects on reproductive system, hepatocytes and kidney cells [ 3 , 4 , 5 ]. When ZEA enters the body of either animals or human beings, it passes through the hepatic and systemic vessels before reaching another target organ [ 3 ].…”

“…Many studies have shown that ZEA and its metabolites may be ingested and lead to various harmful effects on reproductive system, hepatocytes and kidney cells [ 3 , 4 , 5 ]. When ZEA enters the body of either animals or human beings, it passes through the hepatic and systemic vessels before reaching another target organ [ 3 ]. The liver has a significant role in carrying out detoxification of foreign substances along with elimination of metabolites.…”