Deoxynivalenol (DON or vomitoxin) is a trichothecene mycotoxin commonly found in cereal grains that adversely affects growth and immune function in experimental animals. A competitive enzyme-linked immunosorbent assay (ELISA) was used to monitor the kinetics of distribution and clearance of DON in tissues of young adult B6C3F1 male mice that were orally administered 25mg/kg bw of the toxin. DON was detectable from 5 min to 24h in plasma, liver, spleen and brain and from 5 min to 8h in heart and kidney. The highest DON plasma concentrations were observed within 5-15 min (12 microg/mL) after dosing. There was rapid clearance following two-compartment kinetics (t(1/2)alpha=20.4 min, t 1/2 beta=11.8h) with 5% and 2% maximum plasma DON concentrations remaining after 8 and 24h, respectively. DON distribution and clearance kinetics in other tissues were similar to that of plasma. At 5 min, DON concentrations in mug/g were 19.5+/-1.9 in liver, 7.6+/-0.5 in kidney, 7.3+/-0.8 in spleen, 6.8+/-0.9 in heart and 0.8+/-0.1 in the brain. DON recoveries in tissues by ELISA were comparable to a previous study that employed (3)H-DON and 25mg/kg bw DON dose. The ELISA was further applicable to the detection of DON in plasma of mice exposed to the toxin via diet. This approach provides a simple strategy that can be used to answer relevant questions in rodents of how dose, species, age, gender, genetic background and route/duration of exposure impact DON uptake and clearance.
Macrocyclic trichothecene mycotoxins produced by indoor air molds potentially contribute to symptoms associated with damp building illnesses. The purpose of this investigation was to determine (1) the kinetics of nasal inflammation and neurotoxicity after a single intranasal instillation of roridin A (RA), a representative macrocyclic trichothecene; and (2) the capacity of lipopolysaccharide (LPS) to modulate RA's effects. C57Bl/6 female mice were intranasally instilled once with 50 mul of RA (500 mug/kg body weight [bw]) in saline or saline only and then nose and brain tissues were collected over 72 h and processed for histopathologic and messenger RNA (mRNA) analysis. RA-induced apoptosis specifically in olfactory sensory neurons (OSNs) after 24 h postinstillation (PI) causing marked atrophy of olfactory epithelium (OE) that was maximal at 72 h PI. Concurrently, there was marked bilateral atrophy of olfactory nerve layer of the olfactory bulbs (OBs) of the brain. In the ethmoid turbinates, upregulated messenger RNA (mRNA) expression of the proapoptotic gene FAS and the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, IL-1, and macrophage inhibitory protein-2 was observed from 6 to 24 h PI, whereas expression of several other proapoptotic genes (PKR, p53, Bax, and caspase-activated DNAse) was detectable only at 24 h PI. Simultaneous exposure to LPS (500 ng/kg bw) and a lower dose of RA (250 mug/kg bw) magnified RA-induced proinflammatory gene expression, apoptosis, and inflammation in the nasal tract. Taken together, the results suggest that RA markedly induced FAS and proinflammatory cytokine expression prior to evoking OSN apoptosis and OE atrophy and that RA's effects were augmented by LPS.
Consumption of deoxynivalenol (DON), a trichothecene mycotoxin commonly detected in cereal-based foods, causes impaired growth in many animal species. While growth retardation is used as a basis for regulating DON levels in human food, the underlying mechanisms remain poorly understood. Oral exposure of mice to DON rapidly induces multiorgan expression of proinflammatory cytokines, and this is followed by upregulation of several suppressors of cytokine signaling (SOCS), some of which are capable of impairing growth hormone (GH) signaling. The purpose of this study was to test the hypothesis that impairment of the GH axis precedes DON-induced growth retardation in the mouse. Subchronic dietary exposure of young (4-week old) mice to DON (20 ppm) over a period of 2-8 weeks was found to (1) impair weight gain, (2) result in a steady-state plasma DON concentration (40-60 ng/ml), (3) downregulate hepatic insulin-like growth factor acid-labile subunit (IGFALS) mRNA expression, and (4) reduce circulating insulin-like growth factor 1 (IGF1) and IGFALS levels. Acute oral exposure to DON at 0.5-12.5 mg/kg body weight (bw) markedly suppressed hepatic IGFALS mRNA levels within 2 h in a dose-dependent fashion, whereas 0.1 mg/kg bw was without effect. DON-induced IGFALS mRNA upregulation occurred both with and without exogenous GH treatment. These latter effects co-occurred with robust hepatic suppressors of cytokine signaling 3 upregulation. Taken together, these data suggest that oral DON exposure perturbs GH axis by suppressing two clinically relevant growth-related proteins, IGFALS and IGF1. Both have potential to serve as biomarkers of effect in populations exposed to this common foodborne mycotoxin.
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