Description: Das Projekt "Apoptose, ein wichtiger biologischer Umschlagspunkt zur Verfeinerung und Verbesserung der In-vitro-Abschaetzung der Cytotoxizitaet und Gentoxizitaet von Umweltschadstoffen" wird vom Umweltbundesamt gefördert und von Universität Konstanz, Fakultät für Biologie durchgeführt. Mutagenic testing of chemicals and drugs approved by most regulatory authorities (OECD, EEC) involves a tiered system. In doing such tests, some biological parameters (i e mitotic index and cell necrosis) are usually considered. However, it has now become apparent that low level exposure to chemicals may interfere with the regulation of natural cell death, apoptosis. Current cytotoxicity tests do not identify apoptotic cells and this mode of death is typically elicited under milder conditions than those required to produce cell necrosis. Apoptosis. significantly contributes to the organism defence against the persistence of cells with extensive DNA damage or mutations. Removal of heavily compromised cells by apoptosis is essential to prevent a potential spreading of mutated clones. However, if apoptosis is inhibited, an increased fraction of damaged cells carrying genotoxic lesions may survive. This would significantly increase the risk of proliferation of pre-cancer cells. Therefore, chemical and physical agents that possess mutagenic activity, but suppress apoptosis represent a greater danger than others, which can trigger apoptosis, besides their genotoxic effect. Briefly, the project has been designed to decide on the relevance of apoptosis in model cell systems currently used for genotoxicity and cytotoxicity testing. This will be useful in deciding whether the detection of apoptosis should form part of any integrated assessment of chemical toxicity. The results of this project will also help in elucidating some mechanisms involved in the activation or suppression of the apoptotic process by environmental pollutants and chemicals. Finally, we plan to establish whether individual genetical susceptibility to apoptosis will modify the sensitivity of biological test systems (both in vitro and in vivo) to persistent genotoxic or cytotoxic damage. We will examine chemical compounds with known genotoxic and/or cytotoxic effects including: monofunctional and bifunctional alkylating agents, and mercury in its organic and inorganic form. The biological experimental systems will consist of human peropheral blood lymphocytes obtained from healthy donors and cell lines sensitive of resistant to apoptosis to the normal apoptotic function. Cells used routinely for mutagenicity tests will also be utilized e g chinese hamster cells (CHO, C79, CHL) mouse lymphoma cells human hepatoma cells (Hep G2) and HeLa cells. Primary rat or mouse neuronal cultures (cerebellar or cortical) will be employed for the assessment of neurotoxic agents such as inorganic and organic mercury. In addition, genetically manipulated cells (i e, cells transfected with BCL2 and BL41 American Burkitt tumor line transfected with 95-8 strain of the EBV) will be used to study resistance to apoptosis. Lymphoblastoid cell lines from normal donors or from patients affected by Ataxia telegectasia of Fanconi disease will also be used.
Types:
SupportProgram
Origin: /Bund/UBA/UFORDAT
Tags: Konstanz ? Hamster ? Organische Quecksilberverbindung ? Biopharmazeutikum ? Arzneimittel ? Aufsichtsbehörde ? DNA ? Mutagenität ? Quecksilber ? Anorganische Quecksilberverbindung ? Schadstoffwirkung ? Genotoxizität ? Kanzerogenitätsprüfung ? Maus ? OECD ? Ratte ? Umweltchemikalien ? Zytotoxizität ? Messverfahren ? in vitro ? Chemikalienprüfung ? Biotest ? Studie ? Tumor ? Mensch ? Chemische Verbindung ? Blut ? Physikalische Einwirkung ? Chemikalien ? Organismen ? Persistenz ? Kenngröße ? Krankheit ? Risiko ? Schadstoff ? Lymphozyten ?
Region: Baden-Württemberg
Bounding box: 9° .. 9° x 48.5° .. 48.5°
License: cc-by-nc-nd/4.0
Language: Deutsch
Time ranges: 1996-04-01 - 1999-03-31
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