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P05-24 Development of a generic pregnancy PBPK model for mouse: application to neurotoxic molecules
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International audience. An increasing number of studies are raising concerns about the potential effects of environmental pollutants on neurodevelopment through maternal exposure. Mice are commonly used in neurodevelopmental studies, but the observed effects are rarely linked to internal concentrations of substances in the fetal brain. It is therefore relevant to account for pre-gestational and maternal chemical exposures to better characterize the fetal exposure, particularly during the critical window of fetal brain development. This can be done using Physiologically Based Pharmacokinetic (PBPK) models which are useful tools to predict the pharmacokinetic behavior of xenobiotics in an organism. A few PBPK models exist for the pregnant mouse, but these often assume constant maternal weight throughout pregnancy and do not include pre-pregnancy exposures. We have developed a generic pregnancy PBPK model for mouse to determine the concentration in the fetal brain resulting from maternal oral exposure to various chemicals. This model considers seven compartments for the pregnant mouse and five for the fetus including a brain compartment. The model describes the growth of maternal weight gain since birth, organ volumes and changes in blood flow. A sensitivity analysis was carried out using the Sobol method which shows that physico-chemical parameters are the most sensitive. The generic aspect of the model, i.e., its applicability to a wide range of chemical families, was demonstrated on five molecules with different physico-chemical properties: PCB 153, PCDD, dieldrin, DDE and arsenic. These molecules have been identified in a recent study as effect drivers of neurodevelopmental and thyroid risk. The model predicts the internal chemical kinetics of these five chemicals in the fetal brain throughout the neurodevelopmental window. In combination with the data obtained from in vitro studies on human neuronal cells, the in vitro to in vivo extrapolation with this p-PBPK model could be used to investigate developmental neurotoxicology.
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