Projet Hemi-Breaks-T : Métaux lourds et cassures de l’ADN

**Métaux lourds et cassures de l’ADN sur différents tissus humains et non humains

 

[(

Durée : 2011 - 2015

Budget : 140 k€ à ISTerre

Porteur du Projet : INSERM (Lyon)

Equipe ISterre impliquée :
 Géochimie 4D

Contact ISterre : Constance Bochot, Laurent Charlet.

Collaborations :
 U836Radiobiology Group for DSB repair and signalling analyses,
 the CEA-DSV-LRO lab for the cytogenetics ;
 the CNRS-ISTerre for the metal speciation analyses ;
 the IRSN-SECRE for the wors on ecosystems

)]

 

Heavy metals are abundantly used in a number of industrial activities such as mining and metallurgy, fertilizers, paints, plastics stabilizers, cigarettes, batteries and, more recently, in manufacturing of high-tech products such as mobile phones and CD/DVDs.

Metals (e.g. Cr, Se) and corresponding inorganic nanoparticles (e.g. Se°) represent therefore an actual problem of public health throughout two major features : toxicity and cancer risk. Despite of a considerable number of data, the molecular and cellular bases of the toxicity and/or carcinogenesis of metals remain misknown.

Recently, the development of immunofluorescence has allowed to detect individual DNA damage in each cell nucleus. In parallel, new advances have been made in the understanding of the role of DNA double-strand breaks (DSB), whether non-repaired or misrepaired, in the toxicity and carcinogenesis, respectively.

A number of metals like Fe, Cd, Pb, Zn, Al, Ni, Pd, Cr were shown in a previous project to produce few but severe DSBthat may explain toxicity and genomic instability in human endothelium. Thanks to our new data, we are ready to propose a new system unit with a quantitative scale of toxicity and cancerrisks due to any exposure of metal inducing HEMI-DSBs similarly to the radioprotection Sievert system., ATM, a major actor of the DNA damage repair and signalling, goes from the cytoplasm to the nucleus to control the HEMI-DSB repair via end-joining pathway and inhibits the MRE11 nuclease activity to prevent genomic instability. Interestingly, our groups pointed out that the level of active ATM forms in the cytoplasm and in nucleus are specific to the tissue.

Hence, we proposed here a very ambitious project called HEMI-BREAKS-T that aims to investigate : the chromosome and DNA damage repair and signalling dependent from ATM protein together with the metal speciation in two systems contaminated with metals : HUMAN (brain, skin, lung, liver and blood human cells) and ECOSYSTEM (brain,liver, gonad fish cells).

To this aim, 4 partners will be gathered in this project : the INSERM

The effect of different forms of a given metal (Cr(III), Cr(V) and Cr(VI)) are investigated as well as nanoparticles (e.g. Cr2O3 and Se°).

These studies include :
 Metal speciation, by ESR spectroscopy, in cells contaminated by Cr III, V and VI,
 DSB Repair and Signaling,
Other groups within the programme investigate :
 Cytogenetics
 Consequeces to the ecosystems

This project will provide, for the first time, a coherent and original body of datarelevant for a large number of tissues to better understand the molecular and cellular responses to metal response with the most recent concepts and technology in biochemistry.