Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis

Abstract

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.

Novel Perspective on Mechanism in Muscle Growth Inhibited by Ochratoxin A Associated with Ferroptosis: Model of Juvenile Grass Carp (Ctenopharyngodon idella) In Vivo and In Vitro Trials

“…Patulin (PAT) exposure reduced the downregulation and upregulation of SLC7A11, GPX4, and FTH1 expressions in mouse kidney . After administering ZEA orally to mice, it was found that ZEA inhibited the protein expressions of SLC7A11 and GPX4 and led to the accumulation of lipid peroxides and iron in the testes, which is similar to the present results. DFO is an iron-chelating agent that inhibits ferroptosis by chelating iron .…”

Alleviative Effect of Rutin on Zearalenone-Induced Reproductive Toxicity in Male Mice by Preventing Spermatogenic Cell Apoptosis and Modulating Gene Expression in the Hypothalamic–Pituitary–Gonadal Axis

“…Microscopic examination of the testicular seminiferous epithelial tissue in ZEN-exposed mice depicted structural abnormalities such as loose, hollow, reduced sperm count within seminiferous tubules and irregular arrangement of germ cells, indicative of ZEN-induced damage to testicular integrity. Recent reports by Li et al [ 32 ] suggested that ZEN could influence spermatogenesis through ferroptosis, potentially caused by iron accumulation in testicular tissue, leading to irregular germ cell arrangements in the testes. However, pretreatment with RUT exhibited notable differences in the reproductive epithelium, showing increased structural integrity and more uniform cell arrangements.…”

Effects of Zearalenone on Apoptosis and Copper Accumulation of Goat Granulosa Cells In Vitro

“…In addition to the above-mentioned classical cell death pathway, we wondered if ZEA could alter other aspects that are essential for cell survival, such as the transport of metal ions. Evidence has shown that ZEA can increase the Fe 2+ and Fe 3+ concentration on mice spermatogenesis, leading to a higher ferroptosis level [30]. T-2 toxin promoted ferroptosis by inducing lipid ROS and decreased the expression of solute carrier family 7 member 11 (SLC7A11) [31].…”