Phd Thesis: Integrated High Throughput Approach For The Characterization Of Non Genotoxic...

Universities and Institutes of France

France

September 30, 2022

Description

  • Organisation/Company: ANSES
  • Research Field: Biological sciences › Other
  • Researcher Profile: First Stage Researcher (R1)
  • Application Deadline: 30/09/2022 17:00 - Europe/Brussels
  • Location: France › Fougères
  • Type Of Contract: Temporary
  • Job Status: Full-time
  • Hours Per Week: 35
  • Offer Starting Date: 03/10/2022
  • Scientific and Socioeconomic Context

    Generally genotoxic carcinogens interact directly with DNA and generate mutations of different types. These alterations can be detected using a battery of in vitro and in vivo tests with mainly OECD guidelines. However, it is estimated that 10 to 20% of human carcinogens (IARC Class 1) act according to non-genotoxic mechanisms. However, unlike genotoxic agents, NGTxC compounds are poorly considered by current testing strategies. In addition, unlike genotoxic carcinogens, the molecular mechanisms of toxicity of NGTxC are varied and generally act by secondary mechanisms that do not involve direct interaction with DNA. To date, there is no OECD-approved in vitro screening method for NGTxC chemical molecules, and it is likely that many chemicals with NGTxC potential remain unidentified. In addition, although some indicators may alert to the potential of NGTxC, there are no specific guidelines for NGTxC identification. Given the wide variety of mechanisms associated with NGTxC, it is therefore essential to identify screening strategies to assess relevant mechanisms and early key events in order to generate appropriate hazard characterization. Since a positive result in a given trial does not necessarily indicate a potential capacity of NGTxC, it is also clear that an integrated testing strategy is needed to combine and evaluate a battery of results in vitro.

    Research Hypothesis

    To date, there are no strategies for the identification or characterization of non-genotoxic carcinogenic compounds based solely on an in vitro approach. Indeed, the molecular and cellular mechanisms that contribute to non-genotoxic carcinogenicity are many and varied. Thus, it is therefore essential to identify screening strategies to assess relevant mechanisms and early key events in order to generate appropriate hazard characterization. Given that a single test cannot detect all NGTxC, it is clear that an integrated in vitro testing strategy is needed to combine all the results and decide on the carcinogenic potential. This project will therefore aim to identify relevant in vitro endpoints using high-throughput approaches and validated with chemicals known as NGTxC. These endpoints can then be useful for predicting potential NGTxC activity of other compounds. The use of a combination of high- throughput in vitro approaches to identify key molecular pathways in NGTxC activity will provide a better understanding of the mechanisms of action involved in these responses. In addition, the information generated in the project will be useful in generating a battery of in vitro tests that could contribute to the prediction and hazard assessment of NGTxC compounds.

    Major Objectives of the Thesis

    - Generate specific response profiles of NGTxC reference compounds using a series of markers using an approach based on High Content Analysis (HCA) cellular imaging.

    - Generate specific profiles of cellular responses at the mRNA level of NGTxC reference compounds using a high-throughput transcriptomic approach.

    - Use statistical approaches to high-throughput data to generate specific profiles of NGTxC compounds, or classes of these compounds depending on the mechanism, that could be used to predict the non-genotoxic carcinogenic potential of chemical compounds. The key endpoints identified by this statistical approach will be selected to propose a battery of tests for the evaluation of the danger of NGTxC.

    - Use the battery of tests identified in the previous step to screen a library of compounds for NGTxC activity.

    Scientific and Technical Requirements for the Candidate

    Master 2 in Cellular Biology. Experience in Toxicology, and Cell Culture would be a plus

    This thesis will be carried out in the context of the European project PARC

    Offer Requirements
  • REQUIRED EDUCATION LEVEL
  • Biological sciences: Master Degree or equivalent

  • REQUIRED LANGUAGES
  • FRENCH: Good

    ENGLISH: Good

    Skills/Qualifications

    Experience in Toxicology

    Cell culture

    Immunofluorescence and High Content Analysis

    Statistical Analyses

    Bioinformatics

    Contact Information
  • Organisation/Company: ANSES
  • Department: Toxicology of contaminants - Fougères
  • Organisation Type: Public Research Institution
  • Website: https: // www. anses.fr
  • E-Mail: kevin.hogeveen@anses.fr valerie.fessard@anses.fr
  • Country: France
  • City: Fougères
  • Postal Code: 35306
  • Street: 10B rue C. Bourgelat
  • Phone: +33 (0) 299 172 747