Contribution a l'etude structurale et fonctionnelle de deux proteines de la secretion exocrine du pancreas : la proteine des calculs pancreatiques humains, la lipase pancreatique de porc

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Projet Euromix. Vers une démarche normalisée, à l’échelle européenne, pour évaluer les risques des mélanges de contaminants chimiques.

Ce numéro est constitué d’articles issus du colloque « Contaminants alimentaires – approches émergentes pour connaître et prévenir le risque » qui s’est tenu à Paris le 19 décembre 2018.Through our environment, we are continuously exposed to chemical mixtures. Answering the questionof this impact on our health and that of the environment remains a challenge. The risk assessment ofchemicals for regulatory purposes is mainly based on the assessment of individual products. Whilemethodologies and guidance for assessing risks related to combined exposure to multiple chemicalshave been developed for different regulatory sectors, there is no harmonised and consistent approachto assessing and managing these risks.The EuroMix program develops a strategy of, testing, bioassays and models to assess the risks ofchemical mixtures with a focus on: - Reduction of uncertainties through the generation of hazard data through in vitro testing,- Prioritisation according to hazard (in-silico tools) and/or exposure considerations,- Study of the extrapolation of in vitro tests as reliable alternatives for animal testing,- Development of PB-TK models for in vitro/in vivo extrapolation in the risk assessment ofmixtures,- Development of hazard and exposure models for risk assessment and application of thesemodels to newly generated data.Par notre environnement, nous sommes continuellement exposés à des mélanges de produitschimiques. Répondre à la question de cet impact sur notre santé et celle de l’environnement reste unchallenge, l'évaluation des risques des produits chimiques à des fins réglementaires reposantprincipalement sur l'évaluation des composés pris individuellement. Si des méthodologies et lesdémarches pour évaluer les risques liés à l'exposition combinée à de multiples produits chimiques ontété élaborées pour différents secteurs réglementaires, il n'existe pas d'approche harmonisée etcohérente pour l'évaluation et la gestion de ces risques.Le programme EuroMix1 développe une stratégie de tests, bio-essais et modèles pour évaluer lesrisques des mélanges chimiques en mettant l'accent sur :- La réduction des incertitudes par la production de données sur les dangers par des essais invitro,- L’établissement des priorités en fonction du danger (outils in-silico) et/ou sur des considérationsrelatives à l'exposition,- L’étude de l’extrapolation des essais in vitro comme solutions de rechange fiables pour lesessais sur les animaux,- Le développement de modèles PB-TK d’extrapolation in vitro/in vivo dans l'évaluation desrisques liés aux mélanges,- L’élaboration de modèles de danger et d'exposition pour l'évaluation des risques et appliquerces modèles sur les données nouvellement générées

Le BPS, une bonne alternative au BPA ? Effets métaboliques du BPA et du BPS dans les hépatocytes et les adipocytes - Projet MELBA -

National audienc

Evaluation of three simple direct or indirect carbonyl detection methods for characterization of oxidative modifications of proteins

Among disruptions induced by oxidative stress, modifications of proteins, particularly irreversible carbonylation, are associated with the development of several diseases, including cardiovascular diseases, neurodegenerative diseases, and cancer. Carbonylation of proteins can occur directly or indirectly through the adduction of lipid oxidation products. In this study, three classical and easy-to-perform techniques to detect direct or indirect carbonylation of proteins were compared. A model protein apomyoglobin and a complex mixture of rat liver cytosolic proteins were exposed to cumene hydroperoxide oxidation or adduction to the lipid peroxidation product 4-hydroxynonenal in order to test direct or indirect carbonylation, respectively. The technique using a specific anti-4-hydroxynonenal-histidine adduct antibody was effective to detect in vitro modification of model apomyoglobin and cytosolic proteins by 4-hydroxynonenal but not by direct carbonylation which was achieved by techniques using biotin-coupled hydrazide or dinitrophenylhydrazine derivatization of carbonyls. Sequential use of these methods enabled the detection of both direct and indirect carbonyl modification in proteins, although constitutively biotinylated proteins were detected by biotin-hydrazide. Although rather classical and efficient, methods for carbonyl detection on proteins in oxidative stress studies may be biased by some artifactual detections and complicated by proteins multimerizations. The use of more and more specific available antibodies is recommended to complete detection of lipid peroxidation product adducts on proteins

Chronic exposure to Cytolethal Distending Toxin (CDT) promotes a cGAS-dependent type I interferon response

International audienceThe Cytolethal Distending Toxin (CDT) is a bacterial genotoxin produced by pathogenic bacteria causing major foodborne diseases worldwide. CDT activates the DNA Damage Response and modulates the host immune response, but the precise relationship between these outcomes has not been addressed so far. Here, we show that chronic exposure to CDT in HeLa cells or mouse embryonic fibroblasts promotes a strong type I interferon (IFN) response that depends on the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) through the recognition of micronuclei. Indeed, despite active cell cycle checkpoints and in contrast to other DNA damaging agents, cells exposed to CDT reach mitosis where they accumulate massive DNA damage, resulting in chromosome fragmentation and micronucleus formation in daughter cells. These mitotic phenotypes are observed with CDT from various origins and in cancer or normal cell lines. Finally, we show that CDT exposure in immortalized normal colonic epithelial cells is associated to cGAS protein loss and low type I IFN response, implying that CDT immunomodulatory function may vary depending on tissue and cell type. Thus, our results establish a direct link between CDT-induced DNA damage, genetic instability and the cellular immune response that may be relevant in the context of natural infection associated to chronic inflammation or carcinogenesis