Induction of Cytokine mRNAs in Mice After Oral Exposure to the Trichothecene Vomitoxin (Deoxynivalenol): Relationship to Toxin Distribution and Protein Synthesis Inhibition

The effects of oral exposure to 0, 5, and 25 mg/kg body wt vomitoxin (VT) on cytokine mRNA levels in spleen, Peyer′s patches (PP), liver, kidney, and small intestine were evaluated in B6C3F1 mice at 2 and 4 hr postexposure using RT-PCR in conjunction with Southern hybridization analysis. The abundance of mRNAs for several cytokines was increased in VT-exposed mice with maximal effects occurring in the 25 mg/kg group at 2 hr. Specifically, IL-1β and IL-6 mRNA levels increased in spleen and PP following exposure to VT. TNF-α mRNA levels were markedly elevated in spleen and liver of VT-exposed mice. TGF-β mRNA was increased in treatment kidneys and to a lesser extent in liver and small intestine. IFN-γ mRNAs were elevated according to the rank order: spleen > PP > small intestine > liver > kidney, whereas IL-2 mRNAs were increased primarily in spleen and PP. VT had little effect on abundance of mRNAs for the TH2 cytokines, IL-4 and IL-5, or the housekeeping gene, hypoxanthine guanine ribosyl transferase. In order to relate cytokine mRNA abundance to toxin distribution, mice were administered 5 and 25 mg/kg VT body wt containing [3H]VT and tissue levels were monitored over time. Maximum VT molar equivalents for both doses were found at 30 min or 1 hr in all tissues with a rapid clearance following two-compartment kinetics over 24 hr. When effects of oral VT exposure on in vivo protein synthesis at 3 hr postexposure was measured using [14C]leucine uptake, it was found to be inhibited by ≥20 and ≥50% in tissues of mice receiving 5 and 25 mg/kg VT, respectively. While recovery was observed in tissues of the 5 mg/kg group at 6 hr, protein synthesis was still significantly inhibited (≥70%) at 9 hr for all tissues in the 25 mg/kg group. The results suggest that acute oral VT exposure resulted in the transient elevation of mRNAs for proinflammatory and TH1 cytokines. These effects occurred immediately after peak VT accumulation and concurrently with marked in vivo protein synthesis inhibition.