Toxicology Metabolism and Cellular Signaling (MetaTox)

RESEARCHERS

AGGERBECK Lawrence
AGGERBECK Martine
BENELLI Chantal
COTE Francine
FOREST Claude

LECTURERS

AUDOUZE Karine
ANDREAU Karine
BAROUKI Robert
BLANC Etienne
CHAUVET Caroline
CHADEFAUX-VEKEMANS Bernadette
COUMOUL Xavier
KIM Min-Ji
LE FRERE-BELDA Marie-Aude
LECURU Fabrice
NOIREZ Philippe
SANQUER Sylvia

ENGINEERS

BORTOLI Sylvie
JORNOD Florence
LE-GRAND Béatrice
RUGARD Marylène
TETE Arnaud
TOMKIEWICZ Céline

PhD STUDENTS

BOSCHAT Anne-Claire
DUARTE-HOSPITAL Carolina
FALABERGUE Marion
KOUAL Meriem
LARIGOT Lucie
LOPEZ-SUAREZ Loréna
WU Qier

Doctoral School : MTCI
The team developed three main axes:

1- Characterization of metabolic disruptions associated to cancer phenotype and evolution: our team demonstrated, using human cell models (Caco2, MCF7, HepG2, HepaRG), that mixtures of pollutants promote both the processes leading to an epithelial-mesenchymal transition (EMT) and, in parallel, to a Warburg effect: a) EMT corresponds to the cell transition from an epithelial phenotype to a mesenchymal phenotype observed at the time of gastrulation (development) but also in a pathological context (fibrosis, metastatic cancers); B) The Warburg effect is defined by metabolic changes (increased glycolysis, decreased cellular respiration, high lactate production) favoring tumorigenic processes. Moreover, we setup a new co-culture cell model to study the interplay of tumor cells and adipocytes (INSERM innovation prize).

2- Study of the contextual role of pollutants in the occurrence of chronic liver diseases: Chronic Liver Diseases (CLD) represent a serious public health problem linked to various etiologies (alcohol, obesity…). We have shown, using in vivo mouse models, the essential role of TCDD (TetraChloroDibenzoDioxin) in the occurrence of NASH (Non-Alcoholic SteatoHepatitis) at relatively low doses and short exposure periods in association with high fat intake. We also characterized new pathophysiological biomarkers linked to POPs exposure in the liver (e.g. using an original model of xenografted-contaminated adipose tissue). In parallel, we also demonstrate that hepatic expression of key enzymes involved in CLD (Alcohol Dehydrogenases) is altered by TCDD (and other AhR ligands) and alpha-endosulfan.

These 2 axes are complementary regarding the models used (in vitro and in vivo) and allow the identification of MoA focusing on the AhR signaling pathway. This creates a synergetic and collaborative work within the team members (use of common samples and reagents, various expertise on a common signaling pathway) and optimal information sharing. It permits a reduction of the sacrifices while putting a statistically critical level (according to the 3Rs: Replacement, Reduction, Refinement). The third axis focuses on the developmental roles of the AhR (use of KO models). Exposure to xenobiotic AhR ligands lead to similar pathological manifestations than the ones that occur in KO models, suggesting that such pollutants act as antagonists of endogenous ligands. This could lead to the discovery of unexpected pathological events.

3- Analysis of the physiological functions of AhR in the central nervous system: AhR KO mice develop pathologies that recall certain observations made in the context of exposure to pollutants such as TCDD (e.g. liver fibrosis). We hypothesized that AhR KO models can help to understand certain effects of pollutants by reversing the theory that they are AhR activators to consider them as endogenous ligand antagonists. We have focused our attention on the nervous system, considering the specific expression of AhR in the neurons of invertebrates (see introduction) and demonstrated the key role of AhR in myelination and inflammatory processes and the appearance of a horizontal pendular nystagmus (Intra-unit and intra- site collaborations with Prof. Charbel Massaad, team 8 and Dr. Mathieu Beraneck).