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Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

Bottom Line: Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food.Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada.Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.

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ZEA metabolism.Major biotransformation pathways of zearalenone and zeranol in mammals.
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pone-0113632-g003: ZEA metabolism.Major biotransformation pathways of zearalenone and zeranol in mammals.

Mentions: The first analysis of the in vivo metabolism of ZEA was done by Kiessling & Pettersson [15], who studied the livers of rats dosed with ZEA, and identified two major phases of metabolism: the reduction of the ketone group of zearalenone to zearalenol (ZOL), and the conjugation by glucuronic acid to form glucuronide. These two phases of biotransformation of ZEA have been subsequently confirmed by many researchers such as Migdalof et al.[16], Fitzpatrick et al.[17], and Bories et al.[18] and are generally regarded as Phase I and Phase II metabolic processes. Fitzpatrick et al.[17] analyzed the metabolism of zearalenone and found α-zearalenol to be the major metabolite in the feces and the conjugated glucuronides to be the major metabolites in the urine. Migdalof et al.[16] found zearalanone (ZAN) and some conjugated glucuronides in the urine of various species after ingestion of zeranol. They also found some unknown metabolites in the urine, which were later confirmed to be catechols formed by aromatic hydroxylation on the zearalenone phenolic ring [19]. Fig. 3 summarizes the major metabolic pathways of zearalenone and zearalenol. The biotransformation of zearalenone or zeranol, especially the conversion extents to various metabolites formed, were, however, found to vary widely across species, making the task of inter-species scaling very difficult. The extents and rates of various metabolic reactions are important because the metabolites of ZEA vary in their estrogenic potential. The estrogenicity of the compounds has been found to be in the order: α-ZAL> α-ZOL> β-ZAL> ZEA> β-ZOL.


Physiologically-based toxicokinetic modeling of zearalenone and its metabolites: application to the Jersey girl study.

Mukherjee D, Royce SG, Alexander JA, Buckley B, Isukapalli SS, Bandera EV, Zarbl H, Georgopoulos PG - PLoS ONE (2014)

ZEA metabolism.Major biotransformation pathways of zearalenone and zeranol in mammals.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256163&req=5

pone-0113632-g003: ZEA metabolism.Major biotransformation pathways of zearalenone and zeranol in mammals.
Mentions: The first analysis of the in vivo metabolism of ZEA was done by Kiessling & Pettersson [15], who studied the livers of rats dosed with ZEA, and identified two major phases of metabolism: the reduction of the ketone group of zearalenone to zearalenol (ZOL), and the conjugation by glucuronic acid to form glucuronide. These two phases of biotransformation of ZEA have been subsequently confirmed by many researchers such as Migdalof et al.[16], Fitzpatrick et al.[17], and Bories et al.[18] and are generally regarded as Phase I and Phase II metabolic processes. Fitzpatrick et al.[17] analyzed the metabolism of zearalenone and found α-zearalenol to be the major metabolite in the feces and the conjugated glucuronides to be the major metabolites in the urine. Migdalof et al.[16] found zearalanone (ZAN) and some conjugated glucuronides in the urine of various species after ingestion of zeranol. They also found some unknown metabolites in the urine, which were later confirmed to be catechols formed by aromatic hydroxylation on the zearalenone phenolic ring [19]. Fig. 3 summarizes the major metabolic pathways of zearalenone and zearalenol. The biotransformation of zearalenone or zeranol, especially the conversion extents to various metabolites formed, were, however, found to vary widely across species, making the task of inter-species scaling very difficult. The extents and rates of various metabolic reactions are important because the metabolites of ZEA vary in their estrogenic potential. The estrogenicity of the compounds has been found to be in the order: α-ZAL> α-ZOL> β-ZAL> ZEA> β-ZOL.

Bottom Line: Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food.Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada.Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified.

View Article: PubMed Central - PubMed

Affiliation: Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey, United States of America; Department of Environmental and Occupational Medicine, Rutgers University - Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America; Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey, United States of America.

ABSTRACT
Zearalenone (ZEA), a fungal mycotoxin, and its metabolite zeranol (ZAL) are known estrogen agonists in mammals, and are found as contaminants in food. Zeranol, which is more potent than ZEA and comparable in potency to estradiol, is also added as a growth additive in beef in the US and Canada. This article presents the development and application of a Physiologically-Based Toxicokinetic (PBTK) model for ZEA and ZAL and their primary metabolites, zearalenol, zearalanone, and their conjugated glucuronides, for rats and for human subjects. The PBTK modeling study explicitly simulates critical metabolic pathways in the gastrointestinal and hepatic systems. Metabolic events such as dehydrogenation and glucuronidation of the chemicals, which have direct effects on the accumulation and elimination of the toxic compounds, have been quantified. The PBTK model considers urinary and fecal excretion and biliary recirculation and compares the predicted biomarkers of blood, urinary and fecal concentrations with published in vivo measurements in rats and human subjects. Additionally, the toxicokinetic model has been coupled with a novel probabilistic dietary exposure model and applied to the Jersey Girl Study (JGS), which involved measurement of mycoestrogens as urinary biomarkers, in a cohort of young girls in New Jersey, USA. A probabilistic exposure characterization for the study population has been conducted and the predicted urinary concentrations have been compared to measurements considering inter-individual physiological and dietary variability. The in vivo measurements from the JGS fall within the high and low predicted distributions of biomarker values corresponding to dietary exposure estimates calculated by the probabilistic modeling system. The work described here is the first of its kind to present a comprehensive framework developing estimates of potential exposures to mycotoxins and linking them with biologically relevant doses and biomarker measurements, including a systematic characterization of uncertainties in exposure and dose estimation for a vulnerable population.

Show MeSH
Related in: MedlinePlus