Zearalenone Promotes Cell Proliferation or Causes Cell Death?

Abstract

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.

Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

“…ZEN is more dependent on the activation of the estrogen receptor (ER) signaling pathway, which has an anti-inflammatory [8,11,12], anti-apoptotic and proliferating effect [3,13,14]. ER is a ligand-activated transcriptional factor, and signaling is mainly activated directly upon DNA binding in the estrogen response elements located in target genes, but also indirectly (not involving DNA binding) through interaction with other signaling pathways [15][16][17].…”

“…As the intestine is an estrogen-responding organ, it is important to understand the molecular effect of natural endocrine disruptors such as ZEN. Moreover, due to its ability to induce both cell proliferation and oxidative DNA damage, a link has been suggested between ZEN and cancer promotion in the literature [3].…”

“…ZEN is classified as an endocrine disruptor because it can bind and activate estrogen receptors with hyper-estrogenic effects [2]. Like other endocrine disruptors, ZEN has a dual toxicity: pro-apoptotic effects at high, acute doses, and anabolic effects at low doses during chronic exposure [3]. At the cellular level, the toxic effect of high concentrations of ZEN is independent of estrogen signaling, and is characterized by a high oxidative state that induces apoptosis [3].…”

“…Like other endocrine disruptors, ZEN has a dual toxicity: pro-apoptotic effects at high, acute doses, and anabolic effects at low doses during chronic exposure [3]. At the cellular level, the toxic effect of high concentrations of ZEN is independent of estrogen signaling, and is characterized by a high oxidative state that induces apoptosis [3]. Indeed, ZEN provokes a dose-dependent increase of reactive oxygen species levels, oxidative DNA damage, alteration of the mitochondria, membrane disruption and lipid peroxidation [4][5][6][7].…”

“…As the intestine is an estrogen-responding organ, it is important to understand the molecular effect of natural endocrine disruptors such as ZEN. Moreover, due to its ability to induce both cell proliferation and oxidative DNA damage, a link has been suggested between ZEN and cancer promotion in the literature [3].The toxic effect of ZEN in the intestine has been investigated in the past, mostly using pig as model for humans due to their similar sensitivity and toxicity [26]. The main reason for ZEN sensitivity is that pigs, similar to humans, convert ZEN into the more estrogenically active α-zearalenol [27].…”