Toxicokinetic Studies in Piglets Reveal Age-Related Differences in Systemic Exposure to Zearalenone, Zearalenone-14-Glucoside, and Zearalenone-14-Sulfate.

Juveniles are considered as one of the most vulnerable population groups concerning mycotoxins and their modified forms. The weaning stage is a particularly vulnerable period in the life of mammals, reflected in intestinal and immune dysfunction. The current study investigated the toxicokinetic (TK) characteristics of zearalenone (ZEN), zearalenone-14-glucoside (ZEN14G), and zearalenone-14-sulfate (ZEN14S) in weaned (4-week-old) piglets, by means of oral and intravenous administration of equimolar doses, i.e., 331, 500, and 415 µg/kg bodyweight, respectively. Plasma and urine were sampled pre- and post-administration and were quantitatively analyzed for ZEN, ZEN14G, ZEN14S, and in vivo metabolites by liquid chromatography-high-resolution mass spectrometry. Tailor-made TK models were elaborated to process data. A statistical comparison of the results was performed with TK data obtained in a previously reported study in pigs of 8 weeks of age. Additionally, porcine plasma protein binding was determined to support TK findings. The TK results for ZEN, ZEN14G, and ZEN14S, obtained in 4- and 8-week-old pigs, revealed significant age-related differences, based on differences in intestinal permeability, body fat content, gastrointestinal transit time, and biotransformation, with a special emphasis on an increased absorbed fraction of ZEN14G, i.e., 94 vs 61% in 4- compared to 8-week-old pigs. Since the growing pig has been reported to be a suitable pediatric animal model for humans concerning TK processes, these results may contribute to refine the risk assessment concerning modified ZEN forms in juvenile animals and humans.

Investigation of age-related differences in toxicokinetic processes of deoxynivalenol and deoxynivalenol-3-glucoside in weaned piglets.

Age-related differences in toxicokinetic processes of deoxynivalenol (DON) and deoxynivalenol-3-glucoside (DON3G) were studied. DON3G [55.7 µg/kg bodyweight (BW)] and an equimolar dose of DON (36 µg/kg BW) were administered to weaned piglets (4 weeks old) by single intravenous and oral administration in a double two-way cross-over design. Systemic and portal blood was sampled at different time points pre- and post-administration and plasma concentrations of DON, DON3G and their metabolites were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-high-resolution mass spectrometry (LC-HRMS) methods. Data were processed using tailor-made compartmental toxicokinetic (TK) models to accurately estimate TK parameters. Results were statistically compared to data obtained in a previous study on 11-week-old pigs using identical experimental conditions. Significant age-related differences in intestinal and systemic exposure to both DON and DON3G were noted. Most remarkably, a significant difference was found for the absorbed fraction of DON3G, after presystemic hydrolysis to DON, in weaned piglets compared to 11-week-old piglets (83% vs 16%, respectively), assumed to be mainly attributed to the higher intestinal permeability of weaned piglets. Other differences in TK parameters could be assigned to a higher water/fat body ratio and longer gastrointestinal transit time of weaned piglets. Results may further refine current risk assessment concerning DON and DON3G in animals. Additionally, since piglets possibly serve as a human paediatric surrogate model, results may be extrapolated to human infants.

Insights into In Vivo Absolute Oral Bioavailability, Biotransformation, and Toxicokinetics of Zearalenone, α-Zearalenol, ß-Zearalenol, Zearalenone-14-glucoside, and Zearalenone-14-sulfate in Pigs.

The aim of this study was to determine the toxicokinetic characteristics of ZEN and its modified forms, α-zearalenol (α-ZEL), ß-zearalenol (ß-ZEL), zearalenone-14-glucoside (ZEN14G), and zearalenone-14-sulfate (ZEN14S), including presystemic and systemic hydrolysis in pigs. Crossover pig trials were performed by means of intravenous and oral administration of ZEN and its modified forms. Systemic plasma concentrations of the administered toxins and their metabolites were quantified and further processed via tailor-made compartmental toxicokinetic models. Furthermore, portal plasma was analyzed to unravel the site of hydrolysis, and urine samples were analyzed to determine urinary excretion. Results demonstrate complete presystemic hydrolysis of ZEN14G and ZEN14S to ZEN and high oral bioavailability for all administered compounds, with further extensive first-pass glucuronidation. Conclusively, the modified-ZEN forms α-ZEL, ß-ZEL, ZEN14G, and ZEN14S contribute to overall ZEN systemic toxicity in pigs and should be taken into account for risk assessment.