Iron is an important metal element involved in the regulation of male reproductive functions and has dual effects on testicular tissue. A moderate iron content is necessary to maintain testosterone synthesis and spermatogenesis. Iron overload can lead to male reproductive dysfunction by triggering testicular oxidative stress, lipid peroxidation, and even testicular ferroptosis. Ferroptosis is an iron-dependent form of cell death that is characterized by iron overload, lipid peroxidation, mitochondrial damage, and glutathione peroxidase depletion. This review summarizes the regulatory mechanism of ferroptosis and the research progress on testicular ferroptosis caused by endogenous and exogenous toxicants. The purpose of the present review is to provide a theoretical basis for the relationship between ferroptosis and male reproductive function. Some toxic substances or danger signals can cause male reproductive dysfunction by inducing testicular ferroptosis. It is crucial to deeply explore the testicular ferroptosis mechanism, which will help further elucidate the molecular mechanism of male reproductive dysfunction. It is worth noting that ferroptosis does not exist alone but rather coexists with other forms of cell death (such as apoptosis, necrosis, and autophagic death). Alleviating ferroptosis alone may not completely reverse male reproductive dysfunction caused by various risk factors.

T-2 toxin, the most toxic type A trichothecene mycotoxin, is produced by Fusarium, and is widely found in contaminated feed and stored grains. T-2 toxin is physicochemically stable and is challenging to eradicate from contaminated feed and cereal, resulting in food contamination that is inescapable and poses a major hazard to both human and animal health, according to the World Health Organization. Oxidative stress is the upstream cause of all pathogenic variables, and is the primary mechanism through which T-2 toxin causes poisoning. Nuclear factor E2-related factor 2 (Nrf2) also plays a crucial part in oxidative stress, iron metabolism and mitochondrial homeostasis. The major ideas and emerging trends in future study are comprehensively discussed in this review, along with research progress and the molecular mechanism of Nrf2’s involvement in the toxicity impact brought on by T-2 toxin. This paper could provide a theoretical foundation for elucidating how Nrf2 reduces oxidative damage caused by T-2 toxin, and a theoretical reference for exploring target drugs to alleviate T-2 toxin toxicity with Nrf2 molecules.

The intestinal tract is a target organ for Deoxynivalenol (DON) absorption and toxicity. Mitochondrial homeostasis imbalance is the gut toxicity mechanism of DON. Lycopene (LYC) has intestinal protective effects and can maintain mitochondrial homeostasis in response to various danger signals. The purpose of this study was to explore the protective effect of LYC on DON-induced IPEC-J2 cells damage. These results showed that DON exposure induced an increase in the levels of malondialdehyde and reactive oxygen species (ROS) in IPEC-J2 cells. DON impaired IPEC-J2 cell barrier function and caused mitochondrial dysfunction by inducing mitochondrial permeability transition pore (MPTP) opening, mitochondrial membrane potential (MMP) reducing, destroying mitochondrial fission factors, mitochondrial fusion factors, and mitophagy factors expression. However, adding LYC can reduce the toxic effects of DON-induced IPEC-J2 cells and decrease cellular oxidative stress, functional damage, mitochondrial dynamics imbalance, and mitophagy processes. In conclusion, LYC maintains mitochondrial homeostasis to counteract the IPEC-J2 cells’ toxicity of DON.

T-2 toxin is an unavoidable food and feed contaminant that seriously threatens human and animal health. Exposure to T-2 toxin can cause testosterone synthesis disorder in male animals, but the molecular mechanism is still not completely clear. The MAPK pathway participates in the regulation of testosterone synthesis by Leydig cells, but it is unclear whether the MAPK pathway participates in T-2 toxin-induced testosterone synthesis disorders. In this research, testosterone synthesis capacity, testosterone synthase expression and MAPK pathway activation were examined in male mice and TM3 cells exposed to T-2 toxin. The results showed that T-2 toxin exposure decreased testicular volume and caused pathological changes in the microstructure and ultrastructure of testicular Leydig cells. T-2 toxin exposure also decreased testicular testosterone content and the protein expression of testosterone synthase. In vitro, T-2 toxin inhibited cell viability and decreased the expression of testosterone synthase in TM3 cells, and it decreased the testosterone contents in cell culture supernatants. Moreover, T-2 toxin activated the MAPK pathway by increasing the expression of p38, JNK and ERK as well as the expression of p-p38, p-JNK and p-ERK in testis and TM3 cells. The p38 molecular inhibitor (SB203580) significantly alleviated the T-2 toxin-induced decrease in testosterone synthase expression in TM3 cells and the T-2 toxin-induced reduction in testosterone content in TM3 cell culture supernatants. In summary, p38 mediates T-2 toxin-induced Leydig cell testosterone synthesis disorder.