ABSTRACTIMPACT OF SEX AND AGE ON DEOXYNIVALENOL-INDUCED ANOREXIA USING A MURINE MODELByErica Sue Clark The trichothecene mycotoxin deoxynivalenol (DON, vomitoxin) is produced as a secondary metabolite by the fungus Fusarium graminearum and commonly contaminates grains including corn, wheat, and barley. DON is highly resistant to heat processing and can enter human and animal food. Adverse effects of acute exposure to DON include anorexia, diarrhea, and vomiting in experimental animals. Chronic DON exposure can lead to growth retardation and immunotoxic effects. Mice, commonly used in experimental studies for DON risk assessment, are incapable of vomiting but exhibit feed refusal and body weight suppression following exposure to the toxin. Sex and age comparisons in C57BL6 mice to DON-induced anorexia were examined following acute i.p. and dietary exposure to the toxin. A bioassay for feed refusal was used to compare acute i.p. exposures of 1 and 5 mg/kg bw DON. Greater anorectic responses were seen in male than female mice and in aged mice (22 mos) than adult mice (3 mos). When effects of sex and age on food intake and body weight changes were compared after subchronic dietary exposure to 1, 2.5, and 10 ppm DON, males and aged mice were found again to be more sensitive than females and adults, respectively. To identify contributing factors to sex and age dependent anorectic responses to DON, DON tissue clearance as well as plasma proinflammatory cytokine (IL-6, IL-1β, TNF-α) and satiety hormone (CCK, PYY) responses were measured. When acutely exposed to 1 mg/kg bw DON i.p., male and aged mice displayed elevated DON tissue levels and delayed clearance in comparison with female and adult mice, respectively. When comparing sex differences, a significant increase in IL-6 plasma levels was observed in males while cholecystokinin (CCK) response was higher in females after acute DON exposure. In comparing adult and aged mice, acute DON exposure elicited higher proinflammatory cytokine (IL-6, IL-1β) and satiety hormone (CCK, PYY) responses in the plasma of the aged group compared with the adult group. To further explain sex and age dependent anorectic DON responses, urinary and fecal excretion of the toxin were compared after acute i.p. exposure to 1 mg/kg bw DON. Males and aged mice were found to have slower urinary DON excretion in comparison with female and adult mice, respectively. In contrast, males and aged mice had greater excretion of the total DON dose in feces than female and adult mice, though fecal DON recovery accounted for a small percentage of the total DON dose recovered. Hepatic DON glucuronidation activity was found to be species specific, though sex and age differences were not consistently present. Additionally, renal DON glucuronidation activity by either mouse or mink microsomes was undetectable. Identification of groups that show greater sensitivity to DON exposure and examination of factors related to these differences has the potential to provide important information to accurately assess the risk of DON consumption. The results presented in this dissertation indicate that anorectic responses to DON exposure have the potential to vary due to individual characteristics, including sex and age. Collectively, these findings suggest that sex and advanced life stage should be considered when formulating risk assessments for DON and other trichothecene mycotoxins.
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