Individual method predictive of the dna-breaking genotoxic effects of chemical or biochemical agents

Abstract

A process for evaluating the sensitivity of a tissue taken from an individual to the DNA-breaking toxic effect of at least one chemical or biochemical agent, or of a combination of chemical and / or biochemical agents, comprising the following steps: (a) a working concentration is set for said at least one chemical or biochemical agent, or for chemical and / or biochemical agents included in said combination of chemical and / or biochemical agents; (b) cells are taken from a tissue to be evaluated of an individual; (c) said cells are dispersed and / or amplified so as to obtain a cell sample; (d) saidcell sample is brought into contact with said at least one chemical or biochemical agent (or said combination of chemical and / or biochemical agents) in the working concentration thereof defined in step (a), for a predetermined period of time; (e) the number of double-stand breaks of the DNA, and / or a biomarker representing this number, and / or the number of micronuclei is detected, in the knowledge that steps (b), (c), (d) and (e) must be carried out one after the other, and that step (a) must be carried out before step (e).

Description

technical field [0001] The invention relates to the field of toxicology, more specifically to the field of laboratory gene toxicology methods. The present invention more particularly relates to a new method of predicting cytotoxicity following exposure to chemical elements that directly or indirectly break DNA (particularly certain metals, pesticides and certain active substances used in chemotherapy), and the method Determination and cross-validation of parameters and criteria based on multiple cells and enzymes. Background technique [0002] Accumulating data in the literature indicate that double-strand breaks (DSBs) are the DNA damage most associated with cellular lethality and toxicity, genome instability if they are not repaired, and cancer risk if they are poorly repaired ( Jeggo and Lobrich, "DNA double-strand breaks: their cellular and clinical impact?", Oncogene 26(56) pp. 7717-7719 (2007); Joubert et al. "Radiation biology: major advances and perspectives forrad...

AI Technical Summary

Problems solved by technology

Therefore, approaches for the assessment of toxicity and carcinogenicity risk based on the quantification of DSBs and the functionality of their repair pathways seem promising, but for radiation biologists and genetic toxicologists, DSBs, their repair and signaling The definition of the model is far from a consensus, instead several experiments have demonstrated a quantitative correlation between the number of unrepaired DSBs and the cellular radiosensitivity of human cells using immunofluorescence techniques, and proposed Molecular models of (Joubert et al., "DNA double-strand break repair defects in syndromes associated with acute radiation response: at least two different assays to predict intrinsic radiosensitivity?" (DNA double-strand break repair defects in syndromes associated with acute radiation response: At least two different assays to predict intrinsic radiosensitivity?)", Int. J. Radiation Biology 84(2), pp. 1-19 (2008); Joubert et al., (the above article in 2011)) Most recently, The same group of researchers demonstrated specific responses of certain human tissues to metals (particularly Pb, Cd, Al) (Viau et al., "Cadmium inhibits non-homologous end-joining and over-activates the MRE11-dependent repair pathway Non-homologous end joining and overactivation of MRE11-dependent repair pathways), MutationResearch 654, pp. 13-21 (2008); Gastaldo et al., "Lead contamination results in late and slowly repairable DNA double-strand breaks and impacts upon the ATM -dependent signaling pathways (lead contamination causes late and slowly repairable DNA double-strand breaks and effects on ATM-dependent signaling pathways)", Toxicology Letters 173, pp. 201-214 (2007); Gastaldo et al., "Induction and repair rate of DNA damage: A unified model for describing effects of external and inter nal irradiation and contamination with heavymetals (Induction and repair rates of DNA damage: a unified model for describing the effects of external and internal radiation and heavy metal contamination)", JTheoretical Biology 251, pp. 68-81 (2008)

Therefore, for these reagents, the problem of providing predictive methods for individual genotoxicology remains without an operational solution

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