ROS-Mediated Cell Cycle Arrest and Apoptosis Induced by Zearalenone in Mouse Sertoli Cells via ER Stress and the ATP/AMPK Pathway.

Wang-Long Zheng,Bing-Jie Wang,Yu-Ping Shan,Jian-Fa Bai,Zong-Ping Liu,Xue-Zhong Liu,Jian-Hong Gu,Rui-Long Song,Hui Zou,Jian-Chun Bian,Tao Wang,Ling Wang,Yan Yuan,Guo-Qiang Zhu

doi:10.3390/toxins10010024

Abstract

Zearalenone (ZEA) can perturb the differentiation of cells, reduce the generation of reproductive cells and induce a death of germ cells, but the molecular mechanism remains unclear. In order to investigate the potential mechanism of ZEA-induced cell cycle arrest and apoptosis, we studied the effects of ZEA on cell proliferation, cell-cycle distribution, cell-cycle-related proteins, cell death, cell apoptosis, ROS generation and the ATP/AMPK pathway in Sertoli cells. The role of ROS, ER stress and the ATP/AMPK pathway in ZEA-induced cell-cycle arrest and cell apoptosis was explored by using the antioxidant NAC, ER stress inhibitor 4-PBA and the AMPK inhibitor dorsomorphin, respectively. The results revealed that ZEA inhibited the cell proliferation, influenced the distribution of the cell cycle and induced cell apoptosis through the ATP/AMPK pathway. The ATP/AMPK pathway was regulated by ER stress that was induced by ROS generation after exposure to ZEA. Taking these together, this study provided evidence that ROS regulated the process of ZEA-induced cell cycle arrest and cell apoptosis through ER stress and the ATP/AMPK signal ways.

Highlights

Zearalenone (ZEA), produced by several Fusarium species, can exert estrogen-like activity and cause reproductive dysfunction due to its chemical structure [1,2]
Many studies have showed that ZEA-induced cell apoptosis via endoplasmic reticulum (ER) stress, we found that besides those classical pathways of ER stress-inducing apoptosis, the ATP/AMPK signal way was mediated by ER stress in the process of ZEA-induced cell cycle arrest and apoptosis
Cell proliferation was monitored by the xCELLigence system in real time and cell counting kit-8 (CCK-8) assay

Summary

Introduction

Zearalenone (ZEA), produced by several Fusarium species, can exert estrogen-like activity and cause reproductive dysfunction due to its chemical structure [1,2]. ZEA can perturb the differentiation of cells, reduce the generation of reproductive cells and induce the death of germ cells [3,4]. Animal-derived food including meat, milk and eggs from animals exposed to ZEA or that have been given α-Zearalanol (α-ZAL) to promote their growth may contain several mycotoxins and their metabolites [5,6]. A low dose of ZEA has potential tumor-promoting activity, which can promote cell proliferation and division via down-regulating apoptosis [8,9]. Several studies have showed that treatment with a high dose of ZEA can activate autophagy and apoptosis in mouse and goat Leydig cells [10,11]. ZEA can induce cell death and apoptosis in RAW

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