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Deoxynivalenol (DON) is widely emerging in various grain crops, milk, and wine products, which can trigger different toxic effects on humans and animals by inhalation or ingestion. It also imposes a considerable financial loss on the agriculture and food industry each year. Previous studies have reported acute and chronic toxicity of DON in liver, and liver is not only the main detoxification organ for DON but also the circadian clock oscillator directly or indirectly regulates critical physiologically hepatic functions under different physiological and pathological conditions. However, researches on the association of circadian rhythm in DON-induced liver damage are limited. In the present study, mice were divided into four groups (CON, DON, Bmal1OE, and Bmal1OE + DON) and AAV8 was used to activate (Bmal1) expression in liver. Then mice were gavaged with 5 mg/kg bw/day DON or saline at different time points (ZT24 = 0, 4, 8, 12, 16, and 20 h) in 1 day and were sacrificed 30 min after oral gavage. The inflammatory cytokines, signal transducers, and activators of transcription Janus kinase/signal transducers and activator of transcription 3 (JAKs/STAT3) pathway and bile acids levels were detected by enzyme-linked immunosorbent assay (ELISA), western blotting, and target metabolomics, respectively. The DON group showed significantly elevated interleukin-1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.05 for both) and impaired liver function with rhythm disturbances compared to the CON and Bmal1OE groups. At the molecular level, expressions of some circadian clock proteins were significantly downregulated (P < 0.05 for both) and JAKs/STAT3 pathway was activated during DON exposure, accompanied by indicated circadian rhythm disturbance and inflammatory damage. Importantly, Bmal1 overexpression attenuated DON-induced liver damage, while related hepatic bile acids such as cholic acid (CA) showed a decreasing trend in the DON group compared with the CON group. Our study demonstrates a novel finding that Bmal1 plays a critical role in attenuating liver damage by inhibiting inflammatory levels and maintaining bile acids levels under the DON condition. Therefore, Bmal1 may also be a potential molecular target for reducing the hepatotoxic effects of DON in future studies. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON) is the most prevalent mycotoxin in cereals worldwide. It can cause adverse health effects in humans and animals, and maximum levels in food and feed have been implemented by food authorities based on risk assessments derived from estimated intake levels. The lack of human toxicokinetic data such as absorption, distribution, and elimination characteristics hinders the direct calculation of DON plasma levels and exposure. In the present study, we have, therefore, used in vitro-to-in vivo extrapolation of depletion constants in hepatic microsomes from different species and allometric scaling of reported in vivo animal parameters to predict the plasma clearance [0.24 L/(h × kg)] and volume of distribution (1.24 L/kg) for DON in humans. In addition, we have performed a toxicokinetic study with oral and intravenous administration of DON in pigs to establish benchmark parameters for the in vitro extrapolation approach. The determined human toxicokinetic parameters were then used to calculate the bioavailability (50-90%), maximum concentration, and total exposure in plasma, and urinary concentrations under consideration of typical DON levels in grain-based food products. The results were compared to data from biomonitoring studies in human populations. [ABSTRACT FROM AUTHOR]

Mycotoxins are toxic secondary metabolites produced by a range of fungi and are common contaminants of agricultural crops. These toxins are chemically diverse and structurally stable, enabling them to enter the food chain which can lead to numerous adverse health effects in animals and humans. Although mycotoxin exposure is associated with the development of several cancers, it has proved challenging to show a direct connection between exposure and oncogenic change. This study investigates the in vitro cytotoxicity, molecular mechanisms and secondary signalling responses associated with the exposure to three major mycotoxins, fumonisin B1 (FB1), deoxynivalenol (Don) and zearalenone (Zea). The cytotoxicity of FB1, Don and Zea were investigated in cultured HepG2 and Caco-2 cells using cell viability assays as well as flow cytometry. FB1 proved to be less cytotoxic than its counterparts, while Don and Zea demonstrated high cytotoxicity through an apoptotic mechanism. Expression profiles of 84 genes involved in mediating communication between tumour cells and the cellular mediators of inflammation as well as the innate immune system were also studied. The expression profiles associated with the different mycotoxins were further explored for functional networks, biological functions, canonical pathways, toxicological association as well as to predict network associations between the differentially expressed genes. RT-qPCR revealed the significant differential expression of 46 genes, including the expression of several genes strongly associated with cancer and aberrant inflammatory signalling, after mycotoxin exposure. Aberrant inflammatory signalling seems to be a credible contributing factor that initiates the malignant change observed in cells exposed to mycotoxins. [ABSTRACT FROM AUTHOR]

Trichothecenes are a large family of structurally related toxins mainly produced by Fusarium genus. Among the trichothecenes, T-2 toxin and deoxynivalenol (DON) cause the most concern due to their wide distribution and highly toxic nature. Trichothecenes are known for their inhibitory effect on eukaryotic protein synthesis, and oxidative stress is one of their most important underlying toxic mechanisms. They are able to generate free radicals, including reactive oxygen species, which induce lipid peroxidation leading to changes in membrane integrity, cellular redox signaling, and in the antioxidant status of the cells. The mitogen-activated protein kinases signaling pathway is induced by oxidative stress, which also induces caspase-mediated cellular apoptosis pathways. Several new metabolites and novel metabolic pathways of T-2 toxin have been discovered very recently. In human cell lines, HT-2 and neosolaniol (NEO) are the major metabolites of T-2 toxin. Hydroxylation on C-7 and C-9 are two novel metabolic pathways of T-2 toxin in rats. The metabolizing enzymes CYP3A22, CYP3A29, and CYP3A46 in pigs, as well as the enzymes CYP1A5 and CYP3A37 in chickens, are able to catalyze T-2 toxin and HT-2 toxin to form the C-3′-OH metabolites. Similarly to carboxylesterase, CYP3A29 possesses the hydrolytic ability in pigs to convert T-2 toxin to NEO. T-2 toxin is able to down- or upregulate cytochrome P-450 enzymes in different species. The metabolism of DON in humans is region-dependent. Free DON and DON-glucuronide are considered to be the biomarkers for humans. The masked mycotoxin DON-3-β- d-glucoside can be hydrolyzed to free DON in the body. This review will provide useful information on the progress of oxidative stress as well as on the metabolism and the metabolizing enzymes of T-2 toxin and DON. Moreover, the literature will throw light on the blind spots of metabolism and toxicological studies in trichothecenes that have to be explored in the future. [ABSTRACT FROM AUTHOR]