Limits...
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.

Show MeSH

Related in: MedlinePlus

Model structure.Structure of the PBTK model developed for human subjects.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4256163&req=5

pone-0113632-g004: Model structure.Structure of the PBTK model developed for human subjects.

Mentions: The PBTK model developed here expands upon the physiological compartments considered by Shin et al.[31] and introduces additional physiologically and toxicologically relevant entities, including urine, feces and bile, which can help utilize biomarker data and account for various metabolic endpoints. ZEA, ZAL, their various hydrogenated metabolites and their conjugates are separately considered in this model. Absorption dynamics in the gut and entero-hepatic recirculation of parent compounds and their metabolites are also explicitly modeled. ZEA is known to undergo phase-I and phase-II metabolism both in the liver and in the gut (discussed in the “Exposure and Biotransformation” section) and considerable inter-species differences have been reported in the formation of various metabolites and in their ultimate fate in the body [16], [21]. The model accounts for phase-I and phase-II metabolism separately and considers the metabolites α-ZOL, and β-ZOL of ZEA and α-ZAL, β-ZAL, and ZAN of zeranol and their respective glucuronides (ZEAGLU, α-ZOLGLU, β-ZOLGLU, etc.). Extra-hepatic metabolism of ZEA, especially in the gut, is found to be of considerable importance in the study of ZEA biodistribution [32], [33]. The PBTK model considers gut metabolism (both phase-I and phase-II) of ZEA and ZAL in both rat and human. A model for rats is presented in this section, followed by a whole body PBTK model for human subjects in the section: “Extension of the PBTK model to human subjects”. A total of twelve compounds (six metabolites and their respective conjugated glucuronides) have been considered in this PBTK model and their transport, absorption and mutual bio-transformation has been computed. The twelve compounds are denoted by indices 1 through 12. The rat PBTK model helps validate various mechanistic processes that have been considered. Fig. 4 gives a schematic representation of the model developed here. The balance of all twelve chemicals across the physiological compartments is represented by the following equations, where, subscripts i = 1 to 12 denote ZEA, α-ZOL, β-ZOL, α-ZAL, β-ZAL, and ZAN and their glucuronidated conjugates respectively, and the index T denotes various tissues. denotes the concentration of chemical i in tissue compartment T. denotes vascular flow rate into tissues, denotes biliary flow rate, denotes tissue volumes, and denotes the tissue-blood partition coefficients. The kinetic rate constants, K, are explained in Table 1.(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)


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)

Model structure.Structure of the PBTK model developed for human subjects.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0113632-g004: Model structure.Structure of the PBTK model developed for human subjects.
Mentions: The PBTK model developed here expands upon the physiological compartments considered by Shin et al.[31] and introduces additional physiologically and toxicologically relevant entities, including urine, feces and bile, which can help utilize biomarker data and account for various metabolic endpoints. ZEA, ZAL, their various hydrogenated metabolites and their conjugates are separately considered in this model. Absorption dynamics in the gut and entero-hepatic recirculation of parent compounds and their metabolites are also explicitly modeled. ZEA is known to undergo phase-I and phase-II metabolism both in the liver and in the gut (discussed in the “Exposure and Biotransformation” section) and considerable inter-species differences have been reported in the formation of various metabolites and in their ultimate fate in the body [16], [21]. The model accounts for phase-I and phase-II metabolism separately and considers the metabolites α-ZOL, and β-ZOL of ZEA and α-ZAL, β-ZAL, and ZAN of zeranol and their respective glucuronides (ZEAGLU, α-ZOLGLU, β-ZOLGLU, etc.). Extra-hepatic metabolism of ZEA, especially in the gut, is found to be of considerable importance in the study of ZEA biodistribution [32], [33]. The PBTK model considers gut metabolism (both phase-I and phase-II) of ZEA and ZAL in both rat and human. A model for rats is presented in this section, followed by a whole body PBTK model for human subjects in the section: “Extension of the PBTK model to human subjects”. A total of twelve compounds (six metabolites and their respective conjugated glucuronides) have been considered in this PBTK model and their transport, absorption and mutual bio-transformation has been computed. The twelve compounds are denoted by indices 1 through 12. The rat PBTK model helps validate various mechanistic processes that have been considered. Fig. 4 gives a schematic representation of the model developed here. The balance of all twelve chemicals across the physiological compartments is represented by the following equations, where, subscripts i = 1 to 12 denote ZEA, α-ZOL, β-ZOL, α-ZAL, β-ZAL, and ZAN and their glucuronidated conjugates respectively, and the index T denotes various tissues. denotes the concentration of chemical i in tissue compartment T. denotes vascular flow rate into tissues, denotes biliary flow rate, denotes tissue volumes, and denotes the tissue-blood partition coefficients. The kinetic rate constants, K, are explained in Table 1.(1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)

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