Effect of subacute oral doses of nivalenol on immune and metabolic defence systems in mice

Abstract

-Nivalenol (NIV) is a toxic Fusarium secondary trichothecene metabolite occurring naturally in cereal grains. In order to evaluate the no observed adverse effect level (NOAEL), we tested the effects of a large array of oral doses of this toxin for responses on plasma biochemistry, the immune system and hepatic drug metabolism in mice. C57Bl6 mice received oral doses of toxin (0.014, 0.071, 0.355, 1.774 or 8.87 mg/kg bw) 3 days a week for 4 weeks. Only the highest dose of NIV induced an increase in plasma phosphate, decreases in plasma urea and immunoglobulin M and additional changes like increases in plasma alkaline phosphatase and immunoglobulin G. Interleukin 4 production was increased in cultured murine splenocytes. Regarding liver drug metabolising enzymes, the only glutathione transferase activity accepting 1-chloro-2,4-dinitro-benzene as substrate was transiently increased in mice receiving low doses (0.071 and 0.355 mg/kg bw) of NIV. Regarding the cytochrome P450 monooxygenases, no significant change was observed in ethoxyresorufin O-deethylase activity whereas both methoxyresorufin and pentoxyresorufin O-dealkylase activities were decreased by 38-45% for the highest dose (8.87 mg/kg bw) of NIV. However, when analysed by Western blot analysis, the protein expression of mouse P450 1a, 2b, 2c, 3a and 4a subfamilies was unchanged in animals receiving NIV. In conclusion, the NOAEL of this toxin in our study was 1.774 mg/kg bw, corresponding to an exposure to 5 ppm contaminated food. Indeed hepatotoxicity appears in the only mice treated with a five fold higher oral dose of 8.87 mg/kg bw of NIV. Such exposure levels appear to be by far higher than the maximal natural occurrence measured in European cereals, known to range from 0.34 to 1.86 ppm.mice / nivalenol / immunotoxicity / biotransformation enzymes

Scientific Opinion on risks for animal and public health related to the presence of nivalenol in food and feed

“…per day) increased serum IgG levels (Gouze et al, 2007). In the 90-day sub-chronic toxicity study described earlier, dietary exposure of male F344 rats to the highest dose of 100 mg/kg diet induced a slight increase of IgM (26 % increase), while levels of IgG and IgA did not fluctuate at any dose .…”

“…In order to identify a NOAEL, Gouze et al (2007) tested the effects of different oral doses of nivalenol for effects on plasma biochemistry, the immune system and hepatic drug metabolism in mice. C57Bl6 mice (6 groups of 10 animals) received 0.014 to 8.87 mg nivalenol/kg b.w.…”

In vivo toxicity studies of fusarium mycotoxins in the last decade: A review

“…Indeed hepatotoxicity appeared in mice treated with a five-fold higher oral dose of 8.87 mg/kg bw. Such exposure levels appear to be by far higher than the maximal natural occurrence measured in European cereals, known to range from 0.34 to 1.86 mg/kg (Gouze et al, 2007).…”

“…Trichothecenes are toxic to animals and its exposure has been linked to reproductive disorders in domestic animals (Cortinovis et al, 2013). Because of their effects on the immune system, the exposure of trichothecenes could predispose humans and animals to infectious disease, especially for sensitive human populations like young children, immuno-depressed people and old people (Gouze et al, 2007).…”

“…There is a lack of data regarding the effects of low oral doses of NIV in animal models. Gouze et al (2007) described the NOAEL of NIV in mice as 1.774 mg/kg bw, corresponding to an exposure to 5 mg/kg contaminated feed. Although very few studies describe the effects of chronic exposure of NIV at low doses, several countries have established regulations on trichothecenes where only low limits (0.5 to 2 mg/kg) of contamination in cereals are tolerated (Gouze et al, 2007) (Fig.…”