Top-ranked SNPs associated with total reproductive lifespan (p≤0.10).

<p>Top-ranked SNPs associated with total reproductive lifespan (p≤0.10).</p

Top-ranked SNPs associated with age at menopause (p≤0.10).

<p>Top-ranked SNPs associated with age at menopause (p≤0.10).</p

Top-ranked SNPs associated with net reproductive lifespan (p≤0.10).

<p>Top-ranked SNPs associated with net reproductive lifespan (p≤0.10).</p

Top-ranked SNPs associated with age at menarche (p≤0.10).

<p>Top-ranked SNPs associated with age at menarche (p≤0.10).</p

Descriptive characteristics of the Women’s Circle of Health Study.

<p>Descriptive characteristics of the Women’s Circle of Health Study.</p

Physiologically-Based Toxicokinetic Modeling of Zearalenone and Its Metabolites: Application to the Jersey Girl Study

<div><p>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 <i>in vivo</i> 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 <i>in vivo</i> 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.</p></div

Biomarker-to-food correlation.

<p>(a) Correlation coefficients of median ZEA concentrations in urine predicted for the JGS cohort with number of servings of food consumed from various food groups and (b) Corresponding p-values for the correlation coefficients (Dotted line in figure (b) corresponds to a significance level of 0.05) (Food groups explained in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113632#pone-0113632-t004" target="_blank">Table 4</a>).</p

Dietary contributions to exposure.

<p>Contributions of the various major food groups towards (a) entire diet of the JGS subjects and (b) estimated ZEA dose; major food groups were constituted by combining similar smaller food groups as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113632#pone-0113632-t004" target="_blank">Table 4</a>.</p

Urinary biomarker predictions.

<p>Predicted probability distributions corresponding to higher, lower, and median dietary exposure estimates for the entire cohort of 143 girls for urinary biomarker levels compared with measured values; (a), (c) distributions shown with measured percentages of non-detects in the population, and (b), (d) distributions representing only the samples with detects.).</p

Chemical structures of ZEA and its metabolites.

<p>(a) Compounds of the zeranol family of mycotoxins and their biotransformation pathways (adapted from Kleinova <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113632#pone.0113632-Kleinova1" target="_blank">[29]</a>); The stars represent the relative estrogenic potency of the compounds which is in the order: <i>α</i>-ZAL> <i>α</i>-ZOL> <i>β</i>-ZAL> ZEA> <i>β</i>-ZOL. (b) Zearalenone (ZEA) (bottom) and Zeranol (ZAL) (top) molecules with their structural representation.</p