Development of an integrative modelling approach to evaluate the human foetal internal exposure to a contaminant, applied to Bisphenol A as a probe – Modelexpo

The exposure to xenobiotics during prenatal life is a major concern for toxicologists. Xenobiotic exposure of the foetus during critical windows of development have repeatedly been suggested to be involved in the onset of a variety of biological effects later in life, even when exposure occurs at low doses (Vandenberg et al. 2012). Indeed, the susceptibility of the developing foetus is usually exacerbated by its limited capacity of elimination. A sound interpretation of the human health implications, based on toxicological studies carried out in animal models, requires the knowledge of human blood concentrations of biologically active compounds, to enable their comparison with concentrations measured in animal models, when exposure occurs through the mother. Moreover, the development of a method to predict the extent of human foetal internal exposure to xenobiotics, following the exposure of the mother through food and other environmental sources, is critical to be able ultimately to reach a reasonable risk assessment for major contaminants. Among anthropogenic chemicals, the highly prevalent and widespread exposure to bisphenol A (BPA) is of special concern due to its estrogen-like properties. BPA is also a molecule of special interest, as a model. Indeed, over the last two decades, low doses of BPA have been shown to affect not only the reproductive system, but also energy metabolism, and, possibly, cognitive disorders.
Previous BPA toxicokinetic investigations using the model of the chronically-catheterized pregnant sheep have enabled us to identify the placental transfer from foetus to mother and the specific metabolism of the foeto-placental unit as the major determinants of the foetal internal exposure to the unconjugated (e.g. active) form of BPA. The enzymatic conjugation activities of the foeto-placental unit may account for the observed high levels of BPA conjugated metabolites, predominantly BPA-glucuronide (BPAG), exacerbated by the inability of these metabolites to cross the placental barrier. In this context, our project will take advantage of the toxicokinetic data obtained using the pregnant sheep model, to build a physiologically relevant toxicokinetic model of human foetal exposure. The model will incorporate appropriate data from critical life stages in sheep and humans, e.g., placental transfer from mother to foetus and from foetus to mother, as well as metabolic activities of the foeto-placental unit, with the ultimate aim of being able to predict, in humans, the internal exposure levels to the active form of BPA of target tissues of the foetus.
The accumulation of BPAG in foetal plasma, but also its possible reactivation by the deglucuronidation reactions in foetal tissues, will be addressed through an in vivo approach using the integrated model of the pregnant sheep. From this model, we will aim at characterizing foetal biomarkers of tissue exposure to active BPA, accounting for the process of BPA conjugated hydrolysis and the resulting transient increase in foetal tissue concentrations of BPA at levels compatible with those at which adverse effects may be expressed.
Our project will be designed to follow-up different sensitive endpoints of BPA estrogenic activities. Using non-targeted metabolomics approaches, we will explore the metabolic shifts triggered by foetal exposure to BPA or BPAG, which will be used as phenotypic biomarkers of exposure. The relevance for humans of our findings in the ovine model will be established by the characterization of the overall external human exposure to BPA throughout pregnancy in relation to the concentrations of BPA and metabolites in the maternal and umbilical cord blood, as well as the evaluation of the biomarkers of foetal exposure to BPA, previously identified in the ovine model. This integrated approach will provide insight into BPA risk assessment regarding human exposure and provide relevant tools for the identification of biomarkers of BPA imprinting.