Oxidative damage and disturbance of antioxidant capacity by zearalenone and its metabolites in human cells

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.

Section: Discussionsupporting

confidence: 82%

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

Yoon

Lee²,

Seok

et al. 2019

“…There is evidence to indicate that E 2 /E 1 catechol metabolites are weak genotoxins that contribute to malignant transformations by producing quinones that generate DNA adducts [ 42 ]. Catechol production is the main metabolic pathway of ZEN and its metabolites in many mammals [ 43 ], including humans [ 44 ]. The above could suggest that even small doses of ZEN contribute to CW genotoxicity [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

The Genotoxicity of Caecal Water in Gilts Exposed to Low Doses of Zearalenone

Cieplińska¹,

Gajęcka

Nowak

et al. 2018

Zearalenone is a toxic low-molecular-weight molecule that is naturally produced by moulds on crops as a secondary metabolite. The aim of this study was to determine the genotoxicity of caecal water collected successively from the caecal contents of gilts exposed to low doses (LOAEL, NOAEL, and MABEL) of zearalenone. The experiment was performed on 60 clinically healthy gilts with average BW of 14.5 ± 2 kg, divided into three experimental groups and a control group. Group ZEN5 were orally administered ZEN at 5 μg/kg BW, group ZEN10—10 μg ZEN/kg BW and group ZEN15—15 µg ZEN/kg BW. Five gilts from every group were euthanized on analytical dates 1, 2, and 3. Caecal water samples for in vitro analysis were collected from the ileocaecal region. The genotoxicity of caecal water was noted, particularly after date 1 in groups ZEN10 and ZEN15 with a decreasing trend. Electrophoresis revealed the presence of numerous comets without tails in groups C and ZEN5 and fewer comets with clearly expressed tails in groups ZEN10 and ZEN15. The distribution of LLC-PK1 cells ranged from 15% to 20% in groups C and ZEN5, and from 30% to 60% in groups ZEN10 and ZEN15. The analysis of caecal water genotoxicity during exposure to very low doses of ZEN revealed the presence of a counter response and a compensatory effect in gilts.

“…ZEN and its major metabolites are secondary metabolites of Fusarium fungi that produce cell damage [ 12 , 32 ]. A number of studies have found that ZEN has an inhibitory effect on cell proliferation [ 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

“…Most studies of toxicity have shown that the cytotoxicity of ZEN is determined by the production of ROS, DNA damage, and an increased formation of lipid peroxidation [ 36 , 37 ]. In normal physiological processes, small amounts of ROS are generated as by-products of cellular metabolism, primarily in the mitochondria [ 29 , 32 ]. ROS are highly reactive molecules, among which oxygen-free radicals can destroy cell structures, and increase lipid peroxidation of biofilms [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previous in vitro experiments demonstrate that ZEN directly causes apoptosis through the mitochondrial pathway at low concentrations. Subsequently, numerous studies show that ZEN causes intracellular ROS and MDA levels to rise and ΔΨm decreases, leading to cell apoptosis [ 32 , 60 , 61 ]. Based on these findings, to reveal whether ZEN-induced apoptosis involves ΔΨm, our study focused on detecting ΔΨm in SIEC02 cells by JC-1 fluorescence to detect changes in membrane potential.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protective Effect of N-Acetylcysteine against Oxidative Stress Induced by Zearalenone via Mitochondrial Apoptosis Pathway in SIEC02 Cells

Wang

Zhang

et al. 2018

Zearalenone (ZEN), a nonsteroidal estrogen mycotoxin, is widely found in feed and foodstuffs. Intestinal cells may become the primary target of toxin attack after ingesting food containing ZEN. Porcine small intestinal epithelial (SIEC02) cells were selected to assess the effect of ZEN exposure on the intestine. Cells were exposed to ZEN (20 µg/mL) or pretreated with (81, 162, and 324 µg/mL) N-acetylcysteine (NAC) prior to ZEN treatment. Results indicated that the activities of glutathione peroxidase (Gpx) and glutathione reductase (GR) were reduced by ZEN, which induced reactive oxygen species (ROS) and malondialdehyde (MDA) production. Moreover, these activities increased apoptosis and mitochondrial membrane potential (ΔΨm), and regulated the messenger RNA (mRNA) expression of Bax, Bcl-2, caspase-3, caspase-9, and cytochrome c (cyto c). Additionally, NAC pretreatment reduced the oxidative damage and inhibited the apoptosis induced by ZEN. It can be concluded that ZEN-induced oxidative stress and damage may further induce mitochondrial apoptosis, and pretreatment of NAC can degrade this damage to some extent.