Prediction of human prenatal exposure to bisphenol A and bisphenol A glucuronide from an ovine semi-physiological toxicokinetic model

Glenn Gauderat,Nicole Picard-Hagen,Pierre-Louis Toutain,Rémi Servien,Tanguy Corbel,Marlène Z Lacroix,Catherine Viguié,Véronique Gayrard,Alain Bousquet-Melou,Sylvie Puel

doi:10.1038/s41598-017-15646-5

Abstract

Bisphenol A (BPA) risk assessment is hampered by the difficulty of determining the extent of internal exposure in the human fetus and uncertainties regarding BPA toxicokinetics (TK) in the maternal-fetal unit. A feto-maternal TK model describing BPA and BPA glucuronide (BPAG) disposition in sheep was humanized, using human TK data obtained after d6-BPA administration on a cookie, to predict BPA and BPAG kinetics in the human mother-fetus unit. Validation of the model predictions included the assessed dose proportionality of BPA and BPAG disposition and the similarity between the simulated and measured time courses of BPA and BPAG in fetal rhesus monkeys after BPA maternal dosing. The model predicted fluctuations in fetal BPA concentrations associated with typical maternal exposure to BPA through the diet, with similar trough (0.011 ng/L vs 0.014 ng/L) and lower peak BPA concentrations (0.023 ng/L vs 0.14 ng/L) in fetal than in maternal plasma. BPAG concentrations in fetal plasma were predicted to increase over time to reach a steady value (29 ng/L) reflecting the cumulative BPA dose received by the fetus. Model-predicted BPAG concentrations in fetal plasma are consistent with reported levels in human cord blood that may be considered as relevant markers of the BPA dose entering blood throughout fetal life.

Highlights

Bisphenol A (BPA) is an industrial chemical produced in high volumes and present in a wide variety of consumer products worldwide
Previous studies of BPA toxicokinetics (TK) in fetal sheep and rhesus monkey have shown that fetal Phase II metabolism leads to the production of conjugates, mainly BPA glucuronide (BPAG), which accumulate in the fetal circulation owing to their limited placental permeability[8,9,10,11]
Sarigiannis et al.[26] developed a human mother-fetus physiologically-based toxicokinetic models (PBTK) model parameterized for BPA and BPAG which takes into account the changes in physiological and metabolic parameters that occur during gestation

Summary

Introduction

Bisphenol A (BPA) is an industrial chemical produced in high volumes and present in a wide variety of consumer products worldwide. Sarigiannis et al.[26] developed a human mother-fetus PBTK model parameterized for BPA and BPAG which takes into account the changes in physiological and metabolic parameters that occur during gestation These models have the potential to predict the plasma BPA concentration-time curve, they are complex and labor-intensive to build, and require a sound mechanistic basis that has not been well established for BPA and BPAG in the mother-fetal unit. A semi-physiologically-based BPA-BPAG compartmental model can be built, more and without a plurality of hypotheses, by physiological parameterization of a classical compartmental model[19] This makes it possible to assess the relative contributions of metabolic and placental clearance processes to the fates of BPA and BPAG in the materno-fetal unit, and secondly to fit them to predict the fetal plasma BPA and BPAG concentration-time profiles. The final humanized model was used to predict BPA and BPAG plasma concentrations in the human feto-maternal unit under an exposure scheme corresponding to the latest EFSA epidemiological estimates of human external exposure to date

Methods

Results

Discussion

Conclusion