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. 2018 Jul 1;164(1):218-228.
doi: 10.1093/toxsci/kfy078.

The Influence of Obesity on the Pharmacokinetics of Dioxin in Mice: An Assessment Using Classical and PBPK Modeling

Claude Emond  1   2 , Michael J DeVito  3 , Janet J Diliberto  4 , Linda S Birnbaum  5
Affiliations

The Influence of Obesity on the Pharmacokinetics of Dioxin in Mice: An Assessment Using Classical and PBPK Modeling

Claude Emond et al. Toxicol Sci. .

Abstract

The effects of body fat mass on the elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was examined in mice. When male C57BL/6J mice are fed a high-fat, simple carbohydrate diet (HFD) for 13 weeks, they develop an obese phenotype. In contrast, A/J mice fed an HFD do not become obese. After 13 weeks on a normal diet (ND) or HFD, male C57BL/6J and A/J mice received a single dose by gavage of 0.1 or 5.0 µg of 2,3,7,8-tetrachloro[1,6-3H] dibenzo-p-dioxin per kg body weight. Using classical pharmacokinetics, the blood elimination half-life of TCDD was approximately 10 and 2 times longer in the C57BL/6J on the HFD compared with the mice on the ND at 0.1 and 5.0 μg/kg doses, respectively. The diet did not increase the blood half-life of TCDD in the A/J mice, which did not get obese. Using a physiologically based pharmacokinetic model for TCDD that incorporated experimentally derived percent body fat mass and tissue partition coefficients, as well as data on hepatic sequestration, did not provide accurate predictions to the data and could not explain the increase in half-life of TCDD in the HFD groups. This work demonstrates that obesity influences the half-life of TCDD, but other undetermined factors are involved in its elimination because the increase in body fat mass, decreases in cytochrome P4501A2, and altered partition coefficients could not completely explain the prolonged half-life.

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Figures

Figure 1.
Figure 1.
Growth curves (in grams) for each mouse strain: (A) is C57BL/6J and (B) is A/J, consuming either an ND or an HFD after a single oral dose of vehicle or 0.1 μg or 5.0 μg of TCDD/kg bw. Body weight is presented in grams; days corresponds with the time post-TCDD exposure. For both the ND exposed to vehicle (full black line), 0.1 μg TCDD/kg bw (full dack grey line), and 5.0 μg TCDD/kg bw (full light grey line) μg TCDD/kg bw, and for HFD exposed to vehicle (dash black line), 0.1 μg TCDD/kg bw (dash dark grey line), and 5.0 μg TCDD/kg bw (dash light grey line).
Figure 2.
Figure 2.
Induction of CYP1A2 measured by western blot. A, The impact of an HFD on the expression of CYP1A2 in the vehicle controls normalized to the C57 ND mice at the same time point. B, Fold induction compared with vehicle control at time of necropsy for CYP1A2 for 0.1 and 5.0 µg of TCDD/kg in ND and HFD for the C57BL/6J. C, Fold induction compared with the vehicle control at time of necropsy for CYP1A2 for 0.1and 5.0 µg of TCDD/kg in ND and HFD for the A/J.
Figure 3.
Figure 3.
Amount of TCDD measured in liver and adipose tissue, expressed as % dose/tissue: (A) liver of C57BL/6J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw; (B) adipose tissue of C57BL/6J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw; (C) liver of A/J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw; (D) I adipose of A/J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw. The measurements were collected at 1, 3, 10, 20, 30, and 40 days for all mice; for HFD groups an additional time point at 60 days was added.
Figure 4.
Figure 4.
Amount of TCDD measured in total blood expressed in % dose/tissue: (A) blood compartment for C57BL/6J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw; (B) blood compartment of A/J mice fed an ND or HFD at 0.1 or 5.0 µg/kg bw. The measurements were collected at 1, 3, 10, 20, 30, and 40 days and for HFD groups an additional time point at 60 days.
Figure 5.
Figure 5.
The blood profiles of TCDD in mice expressed in terms of ng of TCDD/g bw with time (in days): (A) represents C57BL/6J mice that received doses of 0.1 or 5.0 µg/kg bw; (B) represents the A/J mice that received doses 0.1 or 5.0 µg/kg bw. Both graphs compared the ND with the HFD for each strain.
Figure 6.
Figure 6.
Simulations of the C57BL/6J mice that were exposed to a single dose of TCDD. For this simulation, we used the same parameters as were utilized in the mouse PBPK model for the TCDD reassessment of 2012 (NCEA, 2012). Figures A and B represent the ND group, where (A) is dose of 0.1 µg TCDD/kg bw and (B) represents the dose of 5.0 µg TCDD/kg bw. Figures C and D represent the HFD group, where (C) is the dose of 0.1 µg TCDD/kg bw and (D) represents the dose of 5.0 µg TCDD/kg bw. Dash light grey lines represent the liver, full black lines are the fat, and full dark grey lines represent the blood.
Figure 7.
Figure 7.
Simulations of the C57HFD mice exposed to a single dose of 0.1 or 5.0 µg TCDD/kg bw. A, The simulation at 0.1 µg TCDD/kg bw. B, The simulation after the exposure of 5.0 µg TCDD/kg bw. Dash light grey lines represent the liver, full black lines are the fat, and full dark grey lines represent the blood. For these simulations, we utilized the variation of bw observed during the experiment and determined the PC during the experiment.
Figure 8.
Figure 8.
Simulations of the A/J mice exposed to a single dose of TCDD. For this simulation, we used the same parameters as were utilized in the mouse PBPK model for the dioxin reassessment (NCEA, 2012). Graphs A and B represent the ND group, where (A) is dose of 0.1 µg TCDD/kg bw and (B) represents the dose of 5.0 µg TCDD/kg bw. Figures C and D represent the HFD group, where (C) is the dose of 0.1 µg TCDD/kg bw and (D) represents the dose of 5.0 µg TCDD/kg bw. Light grey lines represent the liver, black lines are the fat, and dark grey lines represent the blood.
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