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Sex Is a Determinant for Deoxynivalenol Metabolism and Elimination in the Mouse
James J Pestka1,2,3, Erica S Clark4,5, Heidi E Schwartz-Zimmermann6
1Department of Food Science and Human Nutrition, Michigan State University, East Lansing, MI 48824, USA. Pestka@msu.edu.
Abstract:
Based on prior observations that deoxynivalenol (DON) toxicity is sex-dependent, we compared metabolism and clearance of this toxin in male and female mice. Following intraperitoneal challenge with 1 mg/kg bw DON, the dose used in the aforementioned toxicity study, ELISA and LC-MS/MS analyses revealed that by 24 h, most DON and DON metabolites were excreted via urine (49-86%) as compared to feces (1.2-8.3%). Females excreted DON and its principal metabolites (DON-3-, DON-8,15 hemiketal-8-, and iso-DON-8-glucuronides) in urine more rapidly than males. Metabolite concentrations were typically 2 to 4 times higher in the livers and kidneys of males than females from 1 to 4 h after dosing. Trace levels of DON-3-sulfate and DON-15-sulfate were found in urine, liver and kidneys from females but not males. Fecal excretion of DON and DON sulfonates was approximately 2-fold greater in males than females. Finally, decreased DON clearance rates in males could not be explained by glucuronidation activities in liver and kidney microsomes. To summarize, increased sensitivity of male mice to DON's toxic effects as compared to females corresponds to decreased ability to clear the toxin via urine but did not appear to result from differences in toxin metabolism.
Insights
Male mice exhibit decreased deoxynivalenol (DON) clearance and higher toxin levels in organs compared to females. This impaired urinary excretion, not altered metabolism, contributes to male sensitivity to DON toxicity.
Area of Science:
- Toxicology
- Environmental Health
- Animal Science
Background:
- Deoxynivalenol (DON) toxicity exhibits sex-dependent variations.
- Previous studies indicated differential sensitivity to DON between male and female mice.
Purpose of the Study:
- To compare the metabolism and clearance of deoxynivalenol (DON) in male and female mice.
- To elucidate the mechanisms underlying sex-dependent DON toxicity.
Main Methods:
- Intraperitoneal administration of DON (1 mg/kg bw) to male and female mice.
- Quantification of DON and its metabolites using ELISA and LC-MS/MS.
- Analysis of urinary and fecal excretion.
- Assessment of metabolite concentrations in liver and kidney tissues.
- Evaluation of glucuronidation activities in liver and kidney microsomes.
Main Results:
- Urine was the primary route of excretion for DON and its metabolites (49-86%) within 24 hours.
- Females exhibited more rapid urinary excretion of DON and its principal glucuronide metabolites compared to males.
- Higher concentrations of DON metabolites were observed in the livers and kidneys of males (2-4 times) within 1-4 hours post-dosing.
- Trace levels of DON sulfates were detected in females but not males.
- Fecal excretion of DON and its sulfonates was approximately 2-fold greater in males.
- No significant differences in glucuronidation activities were found to explain decreased DON clearance in males.
Conclusions:
- Male mice demonstrate a reduced capacity for urinary DON clearance compared to females.
- Higher toxin burdens in male organs correlate with decreased clearance, potentially explaining their increased sensitivity to DON.
- Differences in toxin metabolism, specifically glucuronidation, do not appear to account for the observed sex-dependent clearance rates.
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