Zearalenone Induces Endoplasmic Reticulum Stress and Modulates the Expression of Phase I/II Enzymes in Human Liver Cells.

Jee Eun Yoon,Wei Nee Cheng,Kwang Yong Lee,Jin Sil Seok,Chang Hee Jeong,Sung Gu Han,Hyuk Cheol Kwon

doi:10.3390/toxins12010002

Abstract

Zearalenone (ZEN) is a mycotoxin produced by Fusarium species; however, its mechanisms of action in human livers have not been fully elucidated. Thus, we investigated the toxic mechanisms of ZEN in human liver cells. HepG2 cells were treated with ZEN (0–40 μg/mL) for up to 24 h. A significant decrease in cell viability was observed after treatment with 20 and 40 μg/mL of ZEN, including a significant increase in apoptosis and reactive oxygen species production. ZEN increased GRP78 and CHOP, and eIF2α phosphorylation, indicating ER stress; elevated transcription of the autophagy-associated genes, beclin1 and LC3, and translation of LC3; and increased phase I metabolism by increasing PXR and CYP3A4. The protein expression level of CYP3A4 was higher with ZEN treatment up to 20 μg/mL, but remained at the control level after treatment with 40 μg/mL ZEN. In phase II metabolism, Nrf2 activation and UGT1A expression were increased with ZEN treatment up to 20 μg/mL. Treating cells with an ER stress inhibitor alleviated ZEN-induced cell death and autophagy, and inhibited the expression of phase I/II enzymes. Overall, high ZEN concentrations can modulate the expression of phase I/II enzymes via ER stress and reduced protein levels in human liver cells.

Highlights

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin from Fusarium species [1]
Key Contribution: Zearalenone is well known to possess estrogenic effects; in this study, we demonstrate that zearalenone induces oxidative stress, apoptosis, endoplasmic reticulum (ER) stress, and autophagy and decreases phase I/II enzymes in human liver cells
A marked difference in cell numbers was not observed with ZEN treatment up to 10 μg/mL

Summary

Introduction

Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin from Fusarium species [1]. ZEN contamination is mainly observed in crops such as corn, rice, wheat, and barley, and exposure to this mycotoxin can lead to genotoxicity, teratogenicity, immunotoxicity, and reproductive disorders [2,3,4]. ZEN has been known to induce liver toxicity in cells and animals, there is a lack of toxicological information regarding its detailed mechanisms in human liver cells [5,6].The liver plays a vital role in detoxifying foreign substances and excreting metabolites from the body [7]. Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin from Fusarium species [1]. ZEN contamination is mainly observed in crops such as corn, rice, wheat, and barley, and exposure to this mycotoxin can lead to genotoxicity, teratogenicity, immunotoxicity, and reproductive disorders [2,3,4]. ZEN has been known to induce liver toxicity in cells and animals, there is a lack of toxicological information regarding its detailed mechanisms in human liver cells [5,6]. When xenobiotics enter the body, the liver secretes numerous enzymes to convert the xenobiotics into more hydrophilic and polar metabolites [8]. These cellular events are referred to as phase

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Conclusion