Sex Is a Determinant for Deoxynivalenol Metabolism and Elimination in the Mouse

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.

Mycotoxin Biomarkers of Exposure: A Comprehensive Review

“…Recently, DON‐sulfates (deoxynivalenol‐3‐sulfate (DON‐3‐sulfate) and deoxynivalenol‐15‐sulfate (DON‐15‐sulfate) were identified after DON incubation in rat liver cells; however, they were only detected in female liver cells (Pestka, Clark, Schwartz‐Zimmermann, & Berthiller, ). These compounds are therefore not suitable as reliable biomarkers.…”

“…So, both results coincided with the in vitro observations (Table ). Also, DON‐sulfates (DON‐3‐sulfate and DON‐15‐sulfate) were identified in the urine from female rodents (Pestka et al., ). Concerning the gender difference, the DON excretion was higher in human females than human males due to a larger presence of glucuronidated forms (DON‐15‐glucuronide and DON‐3‐glucuronide) (Vidal et al., ).…”

“…Concerning the gender difference, the DON excretion was higher in human females than human males due to a larger presence of glucuronidated forms (DON‐15‐glucuronide and DON‐3‐glucuronide) (Vidal et al., ). A rodent trial on DON exposure demonstrated that female animals had a higher UGT‐enzyme expression than males, which suggested a gender difference in the response to DON (Pestka et al., ). Although there was a lower level of DON in male urine, larger DON concentrations in male feces were identified (Pestka et al., ).…”

“…A rodent trial on DON exposure demonstrated that female animals had a higher UGT‐enzyme expression than males, which suggested a gender difference in the response to DON (Pestka et al., ). Although there was a lower level of DON in male urine, larger DON concentrations in male feces were identified (Pestka et al., ). The analysis of DON in rats feces also permitted to identify 3 other DON‐sulfonates (Schwartz‐Zimmermann et al., ) (Table ).…”

Stable Isotope-Assisted Metabolomics for Deciphering Xenobiotic Metabolism in Mammalian Cell Culture

“…The metabolic fate of DON has been studied in humans in vivo (Vidal et al 2018;Warth et al 2013), in animals (Schwartz-Zimmermann et al 2014a;Schwartz-Zimmermann et al 2015;Schwartz-Zimmermann et al 2017;Pestka et al 2017), and also in the Fusarium host plant, wheat (Schmeitzl et al 2015;Kluger et al 2013;Warth et al 2015). Plants use various strategies to detoxify DON including the formation of DON-sulfates (Warth et al 2015), DON-glutathione (DON-GSH) as well as its degradation products DON-S-cysteinylglycine (DON-CysGly) and DON-S-cysteine (DON-Cys) (Kluger et al 2013;Kluger et al 2015).…”