Predicting in vivo gene expression in macrophages after exposure to benzo(a)pyrene based on in vitro assays and toxicokinetic/toxicodynamic models

International audiencePredictive toxicology aims at developing methodologies to relate the results obtained from in vitro experiments to in vivo exposure. In the case of polycyclic aromatic hydrocarbons (PAHs), a substantial amount of knowledge on effects and modes of action has been recently obtained from in vitro studies of gene expression. In the current study, we built a physiologically based toxicokinetic (PBTK) model to relate in vivo and in vitro gene expression in case of exposure to benzo(a)pyrene (BaP), a referent PAH. This model was calibrated with two toxicokinetic datasets obtained on rats exposed either through intratracheal instillation or through intravenous administration and on an in vitro degradation study. A good agreement was obtained between the model's predictions and the concentrations measured in target organs, such as liver and lungs. Our model was able to relate correctly the gene expression for two genes targeted by PAHs, measured in vitro on primary human macrophages and in vivo in rat macrophages after exposure to BaP. Combining in vitro studies and PBTK modeling is promising for PAH risk assessment, especially for mixtures which are more efficiently studied in vitro than in vivo

High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.</p

Effets potentiels de micro-et nanoplastiques sur des cellules humaines: Effet des microplastiques/nanoplastiques sur l'activité des transporteurs membranaires de xénobiotiques

National audienceL’exposition de l’Homme aux micro- et nanoplastiques concerne, en premier lieu, les barrières naturelles du corps ou barrières biologiques comme les barrières intestinale et pulmonaire. Les objectifs du projet TRANSPLAST sont de : 1. Caractériser les effets de particules de micro- et nanoplastiques sur les transporteurs membranaires humains de type ABC et SLC reconnus comme étant impactés par les contaminants chimiques ; 2. Préciser les conséquences en terme de fonctionnement des barrières hépatique et intestinale ; 3. Définir les interactions potentielles des transporteurs membranaires avec des polluants chimiques associés aux micro- et nanoplastiques (ex. bisphénol A, pesticides organochlorés, retardateurs de flamme

Actualités sur les transporteurs hépatiques de médicaments

International audienc

Hydrocarbures aromatiques: Caractérisation des voies de signalisation impliquées dans les effets estrogéniques/anti‐estrogéniques des hydrocarbures aromatiques

Parmi les principaux contaminants de l’environnement figurent les hydrocarbures aromatiques comme la dioxine d’origine industrielle et Les hydrocarbures aromatiques polycycliques (dont le benzo(a)pyrène classé « cancérogène pour l’homme »). Ces molécules sont des perturbateurs endocriniens qui agissent sur la régulation de certains gènes via des interactions complexes. Ce projet de recherche vise à améliorer notre compréhension du mécanisme général d’action des hydrocarbures aromatiques

Exemple d'applications des " omiques "

International audienc

Cytokines as molecular targets for aryl hydrocarbon receptor ligands: implications for toxicity and xenobiotic detoxification.

International audienceINTRODUCTION: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor historically known for regulating expression of several important drug-detoxifying proteins. Besides drug metabolism pathways, cytokines have been recently recognized as targeted by the AhR signaling cascade, which may contribute to toxicity and changes in xenobiotic detoxification caused by AhR agonists. AREAS COVERED: This article summarizes the nature of the main cytokines regulated by AhR ligands and reviews their involvement in toxic effects of AhR ligands, especially in relation with inflammation. The article also discusses the potential implications for drug detoxification pathways. EXPERT OPINION: Even if various cytokines, including inflammatory ones, have already been demonstrated to constitute robust targets for AhR, the exact role played by AhR with respect to inflammation remains to be determined. Further studies are also required to better characterize the molecular mechanisms implicated in regulation of cytokines by AhR ligands and to determine the role that may play AhR-targeted cytokines in alteration of xenobiotic detoxification. Finally, changes in cytokine receptor expression triggered by AhR ligands have additionally to be taken into account to better and more extensively comprehend the role played by AhR in the cytokine/inflammation area