Estrogenic activity of zearalenone, α-zearalenol and β-zearalenol assessed using the E-screen assay in MCF-7 cells

Zearalenone (ZEA), a mycotoxin produced in the genus Fusarium, binds to estrogen receptors (ER) and is therefore regarded as an endocrine disruptor. ZEA has also been found to modulate the proliferation and apoptosis of prostate cancer cells in a dose-dependent manner. This study evaluates whether the effect of a low dose of ZEA (0.1 and 0.001 nM) on the invasion and migration of prostate cancer cell line PC3 is associated with ERs expression. The invasion and migration was evaluated by modified Boyden chamber assay, scratch assay, gelatin zymography, Real Time qPCR (RTqPCR) and Western blot. The involvement of ERs was evaluated with the selective ER antagonists: estrogen receptor α (ERα) antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) and estrogen receptor β (ERβ) antagonist 4-[2–phenyl-5,7–bis (trifluoromethyl) pyrazolo [1,5-a]-pyrimidin-3-yl] phenol (PHTPP). ZEA was found to modulate cell motility dependent on estrogen receptors, particularly ERα. Increased cell migration and invasion were associated with increased MMP-2 and MMP-9 activity as well as the up-regulation of the EMT-associated genes vimentin (VIM), zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and transforming growth factor β 1 (TGFβ1). In conclusion, ZEA might modulate the invasiveness of prostate cancer cells dependently on ERα expression.

Section: Discussionsupporting

confidence: 85%

Estrogen Receptor α Is Crucial in Zearalenone-Induced Invasion and Migration of Prostate Cancer Cells

Kowalska

Habrowska-Górczyńska

Urbanek

et al. 2018

Section: The Molecular Mechanisms Of Zea Promoted the Cell Prolifementioning

confidence: 99%

“…ZEA and its metabolites have structural analogy to estrogen ( Figure 2 ), thus they can bind to estrogen receptors (ERs) and exert the estrogen-like effects [ 34 ]. In vitro, ZEA and its metabolites were flexible enough to bind mammalian estrogenic receptors in human cancer MCF-7 cells at dose ranging from 6.25 to 25 µM [ 34 ]. In vivo, ZEA caused multiple estrogenic toxic actions including interfering the processes of establishing and maintaining pregnancy, such as the decidual response, the embryo migration from oviducts to uteri and the activation of luteal function after giving a daily injections of ZEA (2, 4, and 8 mg/kg) during the pregnancy period in female mice [ 35 ].…”

Section: The Molecular Mechanisms Of Zea Promoted the Cell Prolifementioning

confidence: 99%

“…The estrogenic activities are different and can be ranked as follows: α-ZEL = α-ZAL > ZAN > ZEA = β-ZAL > β-ZEL in human breast cancer cells in vitro [ 36 ]. The reason why α-ZEL showed a stronger estrogenic activity than ZEA and other derivatives is that α-ZEL does not bind to the carrier protein which can increase its ability to bind other receptors such as estrogenic receptors [ 34 ]. An increasing number of studies have suggested that steroid hormones have important regulatory roles in cell proliferation, and estrogen can stimulate different cells growth [ 37 , 38 ].…”

Section: The Molecular Mechanisms Of Zea Promoted the Cell Prolifementioning

confidence: 99%

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Zearalenone Promotes Cell Proliferation or Causes Cell Death?

Zheng

Wang

et al. 2018

Zearalenone (ZEA), one of the mycotoxins, exerts different mechanisms of toxicity in different cell types at different doses. It can not only stimulate cell proliferation but also inhibit cell viability, induce cell apoptosis, and cause cell death. Thus, the objective of this review is to summarize the available mechanisms and current evidence of what is known about the cell proliferation or cell death induced by ZEA. An increasing number of studies have suggested that ZEA promoted cell proliferation attributing to its estrogen-like effects and carcinogenic properties. What’s more, many studies have indicated that ZEA caused cell death via affecting the distribution of the cell cycle, stimulating oxidative stress and inducing apoptosis. In addition, several studies have revealed that autophagy and some antioxidants can reverse the damage or cell death induced by ZEA. This review thoroughly summarized the metabolic process of ZEA and the molecular mechanisms of ZEA stimulating cell proliferation and cell death. It concluded that a low dose of ZEA can exert estrogen-like effects and carcinogenic properties, which can stimulate the proliferation of cells. While, in addition, a high dose of ZEA can cause cell death through inducing cell cycle arrest, oxidative stress, DNA damage, mitochondrial damage, and apoptosis.

“…Even though most of these metabolites and analogues are still lacking of a sufficient toxicological characterization, some of them have proved to be stronger than the parent compounds in triggering the molecular cascade underlying the AOP. As an example, keeping in mind that some members of the zearalenone group bind and activate the estrogen receptors, α-zearalenol was proved able to bind the estrogen receptors more strongly than the parent compound zearalenone [ 28 , 29 ]. Therefore, it can be argued that the relative abundance of the differently active metabolites at the site of action may have a relevant role in determining the magnitude of toxic stimulus triggering, with possible consequences also on the magnitude of the overall toxic effect.…”

Section: Toxicokinetics and Toxicodynamics In Chemicals Risk Assesmentioning

confidence: 99%

Toxicodynamics of Mycotoxins in the Framework of Food Risk Assessment—An In Silico Perspective

Dellafiora

Dall’Asta

Galaverna

2018

Mycotoxins severely threaten the health of humans and animals. For this reason, many countries have enforced regulations and recommendations to reduce the dietary exposure. However, even though regulatory actions must be based on solid scientific knowledge, many aspects of their toxicological activity are still poorly understood. In particular, deepening knowledge on the primal molecular events triggering the toxic stimulus may be relevant to better understand the mechanisms of action of mycotoxins. The present work presents the use of in silico approaches in studying the mycotoxins toxicodynamics, and discusses how they may contribute in widening the background of knowledge. A particular emphasis has been posed on the methods accounting the molecular initiating events of toxic action. In more details, the key concepts and challenges of mycotoxins toxicology have been introduced. Then, topical case studies have been presented and some possible practical implementations of studying mycotoxins toxicodynamics have been discussed.