Zearalenone and alpha-zearalenol inhibit the synthesis and secretion of pig follicle stimulating hormone via the non-classical estrogen membrane receptor GPR30

He, Jing; Wei, Chao; Li, Yueqin; Liu, Ying; Wang, Yue; Pan, Jirong; Liu, Jiali; Wu, Yingjie; Cui, Sheng

doi:10.1016/j.mce.2017.08.010

Cited by 45 publications

(32 citation statements)

References 53 publications

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“…LNCaP cell growth might be modulated by both androgens and estrogens, as reported previously [40]. ERβ activation is believed to decrease the viability of PCa cells [29]. The observed decrease in ROS-positive cells after blocking ERβ might confirm this hypothesis, but this needs to be studied further.…”

Section: Discussionsupporting

confidence: 54%

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ERβ and NFκB—Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells

Kowalska

Habrowska-Górczyńska

Domińska

et al. 2020

Toxins

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Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is commonly expressed in prostate cancer (PCa) cells and is associated with increased proliferation, metastases and androgen independence. Zearalenone (ZEA) is one of the most common mycotoxins contaminating food, which might mimic estrogens and bind to estrogen receptors (ERs). The ratio of androgens to estrogens in men decreases physiologically with age, and is believed to participate in prostate carcinogenesis. In this study, we evaluated the role of NFκB and ERβ in the induction of oxidative stress in human PCa cells by ZEA. As observed, ZEA at a dose of 30 µM induces oxidative stress in PCa cells associated with DNA damage and G2/M cell cycle arrest. We also observed that the inhibition of ERβ and NFΚB via specific inhibitors (PHTPP and BAY 117082) significantly increased ZEA-induced oxidative stress, although the mechanism seems to be different for androgen-dependent and androgen-independent cells. Based on our findings, it is possible that the activation of ERβ and NFΚB in PCa might protect cancer cells from ZEA-induced oxidative stress. We therefore shed new light on the mechanism of ZEA toxicity in human cells.

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Section: Discussionsupporting

confidence: 54%

“…Interestingly, He at al. observed that the inhibitory effect of ZEA (30 µM) on pig follicle stimulating hormone (FSH) was associated with the nonclassical membrane estrogen receptor GPR30 [29]. The possible involvement of GPR30 has also been suggested by others [30].…”

Section: Discussionmentioning

confidence: 88%

ERβ and NFκB—Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells

Kowalska

Habrowska-Górczyńska

Domińska

et al. 2020

Toxins

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“…Because ZEN has been reported to exhibit estrogenic-like effects via either genomic or nongenomic ER-mediated signaling pathways [ 3 , 19 , 20 ], we examined whether ERs in BAECs were also involved in the ZEN-mediated reduction of eNOS protein expression. As shown in Figure 2 , neither ICI 182,780, a specific genomic ER antagonist, nor G-15 and G-36, specific nongenomic ER antagonists, affected the inhibitory effect of ZEN on eNOS protein expression.…”

Section: Resultsmentioning

confidence: 99%

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

Lee

Park

et al. 2020

Toxins

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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.

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“…ZEA and ethinyl estradiol accelerated the vaginal opening and increased uterine weight and antral follicle numbers in the ovary resulting from the increased expression of gonadotropin releasing hormone (GnRH) 16 . Furthermore, ZEA and α-ZOL can also inhibit the synthesis and secretion of follicle stimulating hormone (FSH) in pigs through the non-classical estrogen membrane receptor GPR30 17 .…”

Section: Introductionmentioning

confidence: 99%

Mycotoxin zearalenone exposure impairs genomic stability of swine follicular granulosa cells in vitro

Liu¹,

Wu²,

Sun³

et al. 2018

Int. J. Biol. Sci.

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Zearalenone (ZEA), a metabolite of Fusarium fungi, is commonly found on moldy grains. Because it can competitively combine to estrogen receptor to disrupt estrogenic signaling, it has been reported to have serious adverse effects on animal reproduction systems. In order to explore the genotoxic effects of ZEA exposure on ovarian somatic cells, porcine granulosa cells were exposed to 10 μM and 30 μM ZEA for 24 or 72 h in vitro. The results showed that ZEA exposure for 24 h remarkably reduced the proliferation of porcine granulosa cells in a dose-dependent manner as determined by MTT analysis and flow cytometry. Furthermore, exposure to ZEA for 72 h induced apoptosis, and RNA sequence analysis also revealed that the expression of apoptosis related genes were altered. RT-qPCR, immunofluorescence and western blot analysis further confirmed the expression of DNA damage and repair related genes (γ-H2AX, BRCA1, RAD51 and PRKDC) were increased in ZEA exposed granulosa cells. When the estrogen antagonist, tamoxifen, was added with ZEA in the culture medium, the DNA damage and repairment by ZEA returned to normal level. Collectively, these results illustrate that ZEA disrupts genome stability and inhibits growth of porcine granulosa cells via the estrogen receptors which may promote granulosa cell apoptosis when the DNA repair system is not enough to rescue this serious damage.

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Zearalenone and alpha-zearalenol inhibit the synthesis and secretion of pig follicle stimulating hormone via the non-classical estrogen membrane receptor GPR30

Cited by 45 publications

References 53 publications

ERβ and NFκB—Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells

ERβ and NFκB—Modulators of Zearalenone-Induced Oxidative Stress in Human Prostate Cancer Cells

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

Mycotoxin zearalenone exposure impairs genomic stability of swine follicular granulosa cells in vitro

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