| Deoxynivalenol (DON), a fungal metabolite by Fusarium sp is one of 217 known trichothecenes. DON is the most commonly detected trichothecene in cereals and processed food for human consumption worldwide. In addition, DON can become airborne in the breathing zones of some agricultural workers. Upon exposure, DON is distributed (≤30 min) to tissues, and induces proinflammatory cytokines. Chronic DON exposure reduces weight gain in many species. However, the underlying mechanisms for this effect are less understood, thus creating uncertainties in regulatory limits and human safety assessment. The central hypothesis of this dissertation is that proinflammatory cytokine upregulation is associated with modulation of the growth hormone (GH)/insulin-like growth factor (IGF) axis in DON-exposed mice. Various models of murine DON exposure were used to test this hypothesis. The effects of oral and intranasal DON exposure were compared relative to proinflammatory cytokine upregulation, as a model for foodborne and airborne DON. Regardless of exposure route, DON concentrations rapidly (15 to 30 min) peaked in plasma and tissues, with subsequent (1 h) cytokine mRNA upregulation. However, DON concentrations were greater (1.5 to 3 times) by nasal exposure, and proinflammatory cytokine mRNAs such as IL-1beta, IL-6, and TNF-alpha were also greater (2 to 10 times) following nasal exposure than oral exposure. Based on the transient nature of DON-induced cytokines, additional studies were done to determine DON's capacity to induce suppressors of cytokine signaling (SOCS). DON dose-dependently (1 to 12.5 mg/kg bw) induced several SOCS mRNAs in many tissues. Hepatic SOCS3 mRNA was a sensitive indicator of DON exposure and hepatic SOCS3 protein remained upregulated after cytokine decline (5 h). Since SOCS elevation is associated with hepatic GH impairment, DON-induced modulation of the GH/IGF axis was investigated. DON exposure rapidly (2 h) and dose-dependently (0.5 to 12.5 mg/kg bw) suppressed hepatic insulin-like growth factor acid-labile subunit (IGFALS) mRNA by 60-80%, with or without exogenous GH, and with concurrent hepatic SOCS3 mRNA increase. Chronic dietary DON exposure also impaired hepatic IGFALS mRNA by 65% after wk 8. DON exposure also suppressed circulating IGFALS and associated IGF1 by 66 and 26%, respectively; concurrent with elevation of plasma DON (≤63 ng/ml), and weight gain reduction. Additional studies investigated DON's capacity to reduce IGFALS in mice fed high fat diet (HFD), and diet-induced obese (DIO) mice. Again, dietary DON (5 and 10 ppm) suppressed circulating IGFALS by 18 and 30% in lean mice on HFD; and by 20 and 42% in DIO mice. IGFALS suppression was related to adiposity and weight gain reduction in both models. Taken together, these data indicate that DON sequentially upregulates cytokines and SOCS, but suppresses circulating IGFALS and weight gain in different dietary and physiological conditions. DON also shifted the phenotype of mice on high fat diet towards that of low fat diet. Therefore, circulating IGFALS might be a potential biomarker of DON's effect in mice. Furthermore, the association of IGFALS suppression with weight loss in obese mice suggests that the GH/IGF axis might be a novel target for obesity prevention and control. |
