The mechanisms of molecular and cellular responses to xenobiotics are tackled using three complementary approaches.
1/ Responses of human respiratory epithelium to particle-induced environmental stress (Armelle Baeza (manager), Francelyne Marano, Pascal Roussel, Valentina Sirri-Roussel, Sonja Boland).
Human activity (industry, transport) and especially the use of nanotechnologies results in an increase in the exposure of populations to atmospheric pollutants as well as to engineered nanomaterials. The epithelial cells lining the respiratory tract are the first target of inhaled particles, and develop specific responses to this type of exposure.
Our research aims to relate the biological responses with certain physico-chemical characteristics of the particles (chemical composition, size, specific surface, surface reactivity, crystallinity, shape, oxidative potential…). We study engineered nanoparticles as well as nanoparticles unintentionally produced by combustion (diesel engine, chimney fires) or by wear processes (brake pad).
We attempt to improve understanding of the cellular and molecular mechanisms induced by these particles and especially their ability to generate an oxidative stress related or not to their intrinsic oxidative properties.
Oxidative stress can activate signalling cascades leading to adaptive responses or cell death. We also study the nucleolus, a nuclear domain dedicated to ribosome biogenesis and considered as a sensor of cellular stress.
We favor in vitro approaches to investigate the direct effect of the particles on respiratory epithelial cells by using cell lines as well as primary cultures of the human bronchial epithelium. The latter are able to differentiate in vitro and to develop a mucociliary epithelium that can be preserved in culture for several months allowing performing repeated exposures at low doses and studying long term effects.
In particular, the team focuses on:
- internalisation mechanisms and those of passage of particles through airway epithelial barrier
- adaptive responses (such as the anti-oxidant and pro-inflammatory responses) triggered by particles and the cell signalling pathways involved
- the effect of particles on the repair and protection functions of the epithelial barrier and their impact on the differentiation of the respiratory epithelium using omics approaches especially on the epithelial secretome.
- the modulation of these different effects by the interaction of particles not only with biomolecules (lipids, proteins) forming a corona around particles but also with xenobiotics.
- the effect of the particle-derived oxidative stress on the activity of the nucleolus (transcription of ribosomal genes and transcript maturation) and the activity of the nucleolar Sirtuin Sirt7 (class III Histone deacetylase); Sirt7 activity is analyzed by cellular and biochemical approaches.
Our researches aim to contribute to establish adverse outcome pathways through identifying mechanisms of toxicity and developing 3D culture models.
2/ Metabolic and toxicological enzymology (Jean-Marie Dupret (manager), Fernando Rodrigues-Lima (manager), Florent Busi, Linh-Chi Bui, Justine Renault, Emile Petit).
We aim at characterizing the interactions of xenobiotics with enzymatic pathways.
Among xenobiotics used as models, we focus mainly on aromatic compounds. Arylamine N-acetyltransferases, a family of xenobiotic-metabolizing enzymes, play a major role in the organism’s response to these compounds. In particular, our studies have been concentrated on:
- structural and functional enzymology of the arylamine N-acetyltransferases.
- metabolism and toxicity of the aromatic amines of industrial, pharmacological and toxicological interests. Microbial adaptation and biotransformations.
- understanding the metabolic pathways that may allow microorganisms to be used (bacteria, cosmopolitan fungi) as new tools for the bioremediation of aromatic amine-contaminated soils.
The alterations of enzymatic pathways by xenobiotics are increasingly recognized as sources of metabolic disturbances.
To address these questions we aim at :
- deciphering the molecular mechanisms underlying the impact of certain pesticides on key energy enzymes (glycogen phosphorylase)
- understanding the impact of leukemogen chemicals on major epigenetic enzymes (CREBBP acetyltransferase, SETD2 methyltransferase) at both molecular and functional levels.