Lectures are focused on major mechanisms of effects of foreign compounds in the organisms and the applications as the biomarkers. Presented are the most important biochemical and cellualr processes involved in genotoxic as well as non-genotoxic effects. With respect to the classes of xenobiotics, the importance is focused on major classes of environmental contaminants, newly emerging cytostatic and chemoprotective drugs. Biochemical markers of susceptibility, exposure and effects are described in details. Experimental methods and differences of in vivo and in vitro biomarkers are discussed. Examples of practical applications of use of the biomarkers in toxicology, ecotoxicology, and molecular epidemiology are presented.
1. Mechanisms of toxicity and biomarkers - introduction to effects of xenobiotics in organisms, toxokinetics and toxodynamics. Effects at different organismal levels - importance of biochemical processes. Biomarkers of exposure, effects and susceptibility.
2. Major classification of adverse effects (genotoxicity vs. non-genotoxic mechanisms, organ specific toxicity). Approaches and principles of the studies in vivo and in vitro.
3. Metabolims of xenobiotics. Drug-metabolising enzymes, activation and detoxication. Cytochromes P450 - classes, polymorphism, induction and toxicological importance. Enzymes of phase II of biotransformations. Antioxidant compounds and processes. Biomarkers of exposure and susceptibility.
4. Genotoxic effects. DNA and its importance, mutations and other adverse chemically induced genotoxic effects. Strategies, possibilities and methods of genotoxicity testing. Genotoxicity of xenobiotics in risk assessment. Biomarkers of exposure and effects.
5. General cytotoxicity - necrosis. Common mechanisms of toxicity in cells, adverse effects in energy metabolism, toxicity to biomembranes, specific mechanisms of cytotoxicity. Methods and studies of cytotoxicity in vitro.
7. Programmed cell death - apoptosis. Importance of apoptosis, controling, possibilities of model modulations of basic processes. Inhibition of apoptosis - an important mechanism of toxicity of xenobiotics.
8. Cell proliferation, modulations of signal transductions, cell cycle. Major processes of non-genotoxic carcinogenesis, transformation and clonal expansion, inhibition of intercellular communication (GJIC). Chemically induced carcinogenesis.
9. Methods for detection and studies of non-genotoxic mechanisms. Dioxin like toxicitz, estrogenicity, other mechanisms of endocrine disruption, activation of signalling pathways, oxidative stress, modulation of cell proliferation. Use as biomarkers of exposure and effects.
10. Neurotoxicity and immunotoxicity. Examples and importance of toxic effects, relations of organ-specific toxicity to common biochemical mechanisms of toxic effects. Case studies and methods, specific biomarkers in vivo.
11. Toxicity mechanisms of major xenobiotics: PAHs, PCBs, PCDD/Fs, organochlorine contaminants, detergents, inorganic pollutants, cytostatic and chemoprotective drugs.
MacGregor J.T. et al.: Strategies and testing methods for identifying mutagenic risks. Mutation Research 455, 3-20, 2000.
Gray L.E. et al.: Endocrine screening methods workshop report: Detection of estrogenic and androgenic hormonal and antihormonal activity for chemicals that act via receptor or steroidogenic enzyme mechanisms. Reproductive Toxicology 11, 719-750, 1997.
HOFFMAN, D.J. and B.A. RATTNER. Handbook of Ecotoxicology (Handbook of Ecotoxicology). Boca Raton, FL, USA: CRC Press, 1994. info
Hofmanová J. et al.: Epigenetic mechanisms of the carcinogenic effects of xenobiotics and in vitro methods of their detection. Folia Biologica 46, 165-173, 2000.
Toxicant-Receptor Interactions (M.S. Denison, W.G. Helferich, eds.), Taylor and Francis, 1998.
Altucci L., Gronemeyer H.: Nuclear receptors in cell life nad death. Trends in Endocrinology and Metabolism 12, 460-468, 2001.