Development of a lifetime PBPK model for the female mouse

Development of a lifetime PBPK model for the female mouse: application to neurotoxic molecules through oral exposure during pregnancy and lactation

Paré A1,2, Ratier A1,2, Mhaouty-Kodja S3,4, Chardon K2, Zeman F1,2

1 INERIS, Unit of Experimental Toxicology and Modeling, Verneuil-en-Halatte, France

2 PériTox Laboratory, UMR-I 01 INERIS, Université de Picardie Jules Verne, Amiens, France

3 Sorbonne Université, CNRS, INSERM, Development, Adaptation and Ageing, Dev2A, F75005 Paris, France

4 Sorbonne Université, CNRS, Inserm, Institut de Biologie Paris-Seine, IBPS, F75005 Paris, France

An increasing number of studies are raising concerns about the potential effects of environmental pollutants on neurodevelopment through maternal exposure. A recent risk evaluation of an environmental pollutant mixture present in breast milk (ContaLait study, (Rigourd, 2015)) demonstrated an increased risk for the neurodevelopment of breastfed children. Although mice are widely used in neurodevelopmental studies, the internal concentrations of chemicals in the pup’s brain are rarely measured, limiting the understanding of exposure effects. To address this gap, it is essential to consider maternal and pre-gestational chemical exposures, especially during the critical windows of fetal and early postnatal brain development. Physiologically Based Pharmacokinetic (PBPK) models offer a powerful approach to simulate the toxicokinetics of xenobiotics based on chemical properties and physiological parameters. While several PBPK models exist for mice, none have been tailored to simulate continuous maternal exposure from pre-gestation to lactation. Thus, we developed a generic pregnancy and lactational PBPK model for mice. This model estimates chemical concentrations in the offspring’s brain throughout the neurodevelopmental window resulting from maternal oral exposure, accounting for both in utero and lactational transfer. The model considers seven compartments for the dam and six for the fetus, including a brain compartment. It simulates growth dynamics from birth for the dam and from embryogenesis for the pup, including organ volume changes and blood flow variations. The generic aspect of the model, i.e., its applicability to a wide range of chemical families, was demonstrated on various molecules with different physico-chemical properties including: PFOA, methylmercury, dieldrin, DDE and arsenic. These molecules were identified as neurodevelopmental risk drivers in the ContaLait study (Crepet et al., 2022). This PBPK model will be integrated into an in vivo–in vitro extrapolation (IVIVE) framework, combining in vitro data to better understand how maternal exposure to environmental pollutants contributes to developmental neurotoxicity.

References:

Crepet, A., et al., 2022. Integrating Selection and Risk Assessment of Chemical Mixtures: A Novel Approach Applied to a Breast Milk Survey. Environ Health Perspect. 130, 35001.

Rigourd, V., 2015. Levels of contaminants in human milk (Conta-Lait), NCT01848444.

Keywords: PBPK model, mouse, neurodevelopment, chemical exposure, pregnancy