Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein–protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.

T-2 toxin is a trichothecene mycotoxin of significant danger to humans and animals. Its impact on reproductive toxicity is attributed to oxidative stress, which ultimately leads to cell death. Ferroptosis is a programmed cell death that characterized by lipid peroxidation. This study aimed to investigate the toxic effects of T-2 toxin on mouse testis and the potential mechanism of T-2 toxin-induced ferroptosis. T-2 toxin significantly altered the morphology of the testis and decreased testosterone level, sperm concentration, and increased sperm malformation rate, as well as induced oxidative damage with reactive oxygen species and malondialdehyde accumulated, and activity of superoxide dismutase, glutathione peroxidase decreased. Additionally, T-2 toxin induced ferroptosis by accumulating iron ions, increasing prostaglandin endoperoxide synthase 2, downregulating glutathione peroxidase 4 and ferritin heavy chain 1, as well as manifesting ferroptotic morphological alterations, ultimately leading to testicular impairment. Administration of ferroptosis inhibitor liproxstatin-1 or antioxidant resveratrol effectively mitigated the T-2 toxin-induced ferroptosis and testicular injury. These findings provided novel insights into the fundamental mechanism of T-2 toxin-induced cell death and furnished further proof of the potential therapeutic effect in addressing T-2 toxin-induced testicular impairment.

Growing evidence has revealed the deleterious influence of environmental and food contaminants on puberty onset and development in both animals and children, provoking an increasing health concern. T-2 toxin, a naturally-produced Type A trichothecene mycotoxin which is frequently found in cereal grains and products intended for human and animal consumption, has been shown to impair the reproduction and development in animals. Nevertheless, whether this trichothecene mycotoxin can disturb the onset of puberty in females remains unclear. To clarify this point, infantile female rats were given a daily intragastric administration of vehicle or 187.5 μg/kg body weight of T-2 toxin for five consecutive days from postnatal day 15 to 19, and the effects on puberty onset were evaluated in the present study. The results revealed that the days of vaginal opening, first dioestrus, and first estrus in regular estrous cycle were delayed following prepubertal exposure to T-2 toxin. The relative weights of reproductive organs uterus, ovaries, and vagina, and the incidence of corpora lutea were all diminished in T-2 toxin-treated rats. Serum levels of gonadotropins luteinizing hormone, follicle-stimulating hormone, and estradiol were also reduced by T-2 toxin treatment. The mRNA expressions of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary GnRH receptor displayed significant reductions following exposure to T-2 toxin, which were consistent with the changes of serum gonadotropins, delayed reproductive organ development, and delayed vaginal opening. In conclusion, the present study reveals that prepubertal exposure to T-2 toxin delays the onset of puberty in immature female rats, probably by the mechanism of disturbance of hypothalamic-pituitary-gonadal (HPG) axis function. Considering the vulnerability of developmental children to food contaminants and the relative high level of dietary intake of T-2 toxin in children, we think the findings of the present study provide valuable information for the health risk assessment in children.

The reproductive system has been increasingly implicated as a sensitive target of microwave radiation. Oxidative stress plays a critical role in microwave radiation -induced reproductive damage, though precise mechanisms are obscure. Metformin, a widely used antidiabetic drug, has emerged as an efficient antioxidant against a variety of oxidative injuries. In the present study, we hypothesized that metformin can function as an antioxidant and protect the reproductive system from microwave radiation. To test this hypothesis, rats were exposed to 2.856 GHz microwave radiation for 6 weeks to simulate real-life exposure to high-frequency microwave radiation. Our results showed that exposure to 2.856 GHz microwave radiation elicited serum hormone disorder, decreased sperm motility, and depleted sperm energy, and it induced abnormalities of testicular structure as well as mitochondrial impairment. Metformin was found to effectively protect the reproductive system against structural and functional impairments caused by microwave radiation. In particular, metformin can ameliorate microwave-radiation-induced oxidative injury and mitigate apoptosis in the testis, as determined by glutathione/-oxidized glutathione (GSH/GSSG), lipid peroxidation, and protein expression of heme oxygenase-1 (HO-1). These findings demonstrated that exposure to 2.856 GHz microwave radiation induces obvious structural and functional impairments of the male reproductive system, and suggested that metformin can function as a promising antioxidant to inhibit microwave-radiation-induced harmful effects by inhibiting oxidative stress and apoptosis.