Zearalenone Induces Apoptosis and Autophagy in a Spermatogonia Cell Line

Lee, Ran; Kim, Dong-Wook; Lee, Won Young; Park, Hyun Jung

doi:10.3390/toxins14020148

Cited by 22 publications

(11 citation statements)

References 65 publications

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“…It is well known that multiple cell death pathways, such as apoptosis and autophagy, are involved in the mechanism of ZEA toxicity [ 21 , 22 ]. However, whether necroptosis is a mechanism of cell death in ZEA-triggered toxicity remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Gao

Zhang

et al. 2022

IJMS

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Zearalenone (ZEA) is a fungal mycotoxin known to exert strong reproductive toxicity in animals. As a newly identified type of programmed cell death, necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of lactate dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs necroptosis and powerfully blocked ZEA-induced reactive oxygen species (ROS) generation and mitochondrial dysfunction. The reactive oxygen species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular Ca2+ overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs necroptosis, which may provide a new therapeutic strategy for ZEA poisoning.

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Section: Discussionmentioning

confidence: 99%

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Gao

Zhang

et al. 2022

IJMS

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“…However, when unregulated, it can cause cell death, restoring the autophagy balance could help protect cells from damage. In a spermatogonia cell line, ZEA was found to induce autophagy and apoptosis ( 157 ), while in chicken granulosa cells, similar effects could occur through the MAPK and PI3K-AKT-mTOR signaling pathways ( 158 ). Similarly, OTA treatment can trigger autophagy in a dose-dependent manner ( 159 ) along with higher levels of intracellular ROS but these effects were reversed with a combination of zinc and SeMet ( 160 ).…”

Section: Underlying Mechanism Of Se Against Mycotoxinsmentioning

confidence: 99%

Protective and detoxifying effects conferred by selenium against mycotoxins and livestock viruses: A review

Fang

Liu

2022

Front. Vet. Sci.

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Animal feed can easily be infected with molds during production and storage processes, and this can lead to the production of secondary metabolites, such as mycotoxins, which eventually threaten human and animal health. Furthermore, livestock production is also not free from viral infections. Under these conditions, the essential trace element, selenium (Se), can confer various biological benefits to humans and animals, especially due to its anticancer, antiviral, and antioxidant properties, as well as its ability to regulate immune responses. This article reviews the latest literature on the antagonistic effects of Se on mycotoxin toxicity and viral infections in animals. We outlined the systemic toxicity of mycotoxins and the primary mechanisms of mycotoxin-induced toxicity in this analysis. In addition, we pay close attention to how mycotoxins and viral infections in livestock interact. The use of Se supplementation against mycotoxin-induced toxicity and cattle viral infection was the topic of our final discussion. The coronavirus disease 2019 (COVID-19) pandemic, which is currently causing a health catastrophe, has altered our perspective on health concerns to one that is more holistic and increasingly embraces the One Health Concept, which acknowledges the interdependence of humans, animals, and the environment. In light of this, we have made an effort to present a thorough and wide-ranging background on the protective functions of selenium in successfully reducing mycotoxin toxicity and livestock viral infection. It concluded that mycotoxins could be systemically harmful and pose a severe risk to human and animal health. On the contrary, animal mycotoxins and viral illnesses have a close connection. Last but not least, these findings show that the interaction between Se status and host response to mycotoxins and cattle virus infection is crucial.

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“…Previous studies showed that ZEA not only causes cytotoxicity [ 6 ], genetic toxicity [ 7 ], and immunotoxicity [ 8 ] in domestic animals but also affects the normal operation of the estrogen signaling pathway leading to animal reproductive toxicity [ 9 ]. Previous studies have shown that ZEA exposure can reduce the semen quality of male mice, increase the rate of spermatogenic cell apoptosis, hinder spermatogenesis, and thus impair male reproductive function [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis

Zhu

Cui

Ding

et al. 2022

Animals

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Male reproductive health is critically worsening around the world. It has been reported that the mycotoxin ZEA causes reproductive toxicity to domestic animals and affects spermatogenesis, thereby inhibiting male reproductive function. Ferroptosis is a newly identified type of programmed cell death that is different from apoptosis and it depends on iron accumulation and lipid peroxidation. Whether ferroptosis is linked to ZEA’s detrimental effect on spermatogenesis needs to be further explored. This study clarifies ferroptosis’s involvement in ZEA-induced damage on spermatogenesis. The reproductive injury model used in this study was induced by gavaging male mice in the ZEA treatment group with 30 μg/kg of ZEA for five weeks. Results show that ZEA treatment reduced mouse sperm motility and concentration, destroyed the structure of the seminiferous tubules of the testis, damaged the antioxidant defense system, and blocked spermatogenesis. Ferrostatin-1 (Fer-1) inhibition of ferroptosis partially alleviated ZEA-induced oligozoospermia in mice. In addition, ZEA treatment was found to activate a signaling pathway associated with ferroptosis in mouse testis. ZEA also downregulated the expression of Nrf2, SLC7A11, and GPX4, and decreased the protein expression of SLC7A11 and GPX4, resulting in the accumulation of lipid peroxides and an increase in the level of 4-HNE protein in the testis. Importantly, these changes were accompanied by an increase in the relative contents of Fe2+ and Fe3+. Iron accumulation and lipid peroxidation are the causes of ferroptosis in spermatogenic cells, leading to a decrease in sperm motility and concentration. While the administration of Fer-1 at 0.5 and 1 mg/kg also increased the expression of SLC7A11 and GPX4 proteins by upregulating Nrf2 expression, reducing iron accumulation, and reversing ZEA-induced ferroptosis, Fer-1 at 1.5 mg/kg had the best repairing effect for all parameters. In conclusion, ZEA-induced ferroptosis may be mediated by a notable reduction in Nrf2, SLC7A11 and GPX4 expression levels. Overall, ferroptosis is a novel therapeutic target for mitigating ZEA-induced reproductive toxicity.

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Zearalenone Induces Apoptosis and Autophagy in a Spermatogonia Cell Line

Cited by 22 publications

References 65 publications

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Protective and detoxifying effects conferred by selenium against mycotoxins and livestock viruses: A review

Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis

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