Chemical Mutagens

1 In Vivo Mutagenicity Testing Using Somatic Cells of Drosophila melanogaster.- 1. Introduction.- 2. Basic Developmental Biology of Drosophila.- 3. The Wing Mosaic System.- 3.1. The Genetic Basis of the Wing System.- 3.2. Scoring.- 3.3. Data Analysis.- 3.4. Spontaneous Frequencies of Spots in Different Genetic Backgrounds.- 4. The White/White-Coral Eye Mosaic System.- 4.1. The Genetic Basis of the White/White-Coral System.- 4.2. Scoring.- 4.3. Data Analysis.- 4.4. Background Frequencies of Spots.- 5. The Unstable White-Zeste Eye Mosaic System.- 5.1. The Genetic Basis of the Unstable White-Zeste System.- 5.2. Scoring.- 5.3. Data Analysis.- 5.4. Background Frequencies of Spots.- 5.5. Mechanism.- 6. Exposure Techniques.- 6.1. Egg Collection.- 6.2. Collection of Larvae.- 6.3. Feeding.- 6.4. Inhalation.- 6.5. Injection.- 6.6. Solvents.- 6.7. Dosimetry.- 7. Discussion.- 7.1. Genetic Mechanisms.- 7.2. Differences between Genotypes.- 7.3. Toxic Effects and Cell Death.- 7.4. Status of Validation.- 7.5. Comparison of Germ Cells versus Somatic Cells.- 7.6. Comparison of Drosophila Tests with Other Assay Systems.- 7.7. Future Developments.- 7.8. Test Performance.- 8. Conclusions.- 9. References.- 2 Structural and Metabolic Parameters Governing the Mutagenicity of Polycyclic Aromatic Hydrocarbons.- 1. Introduction.- 1.1. Scope of This Review.- 1.2. Terms, Short Names, and Abbreviations.- 1.3. Overview of the Metabolism of PAHs in Mammals.- 2. Activation Pathways of PAHs.- 2.1. Requirement of Activation for Mutagenicity to Occur.- 2.2. Activation to Monofunctional Epoxides.- 2.3. Activation to Vicinal Diol-Epoxides.- 2.4. Activation to Benzylic Esters.- 2.5. Activation to Free Radicals.- 2.6. Other Activation Pathways.- 3. Contribution of Different Activation Pathways to the Mutagenicity of PAHs.- 3.1. DNA Adducts.- 3.2. Modified Test Compounds to Elucidate the Activation Process.- 3.3. Use of Diagnostic Enzymes and Enzyme Inhibitors.- 4. Metabolic Control of Mutagenic Intermediates of PAHs.- 4.1. Mutagenicity Experiments with Subcellular Metabolizing Systems.- 4.2. Mutagenicity Experiments Using Intact Cells as the Metabolizing Systems.- 5. Summary and Conclusions.- 6. Addendum: Recent Developments.- 6.1. Mutagenicity of Quinones.- 6.2. Mutagenicity of Phenol-diol-epoxides.- 7. References.- 3 Chromosomal Mutations: The Genetic Approach.- 1. Introduction.- 2. The Main Categories of Chromosomal Mutation.- 2.1. Numerical Anomalies.- 2.2. Structural Anomalies.- 3. Genetic Detection of Aneuploidy in the Mouse.- 3.1. Sex-Chromosomal Aneuploidy.- 3.2. Autosomal Aneuploidy.- 4. Reciprocal Translocations: Detection and Analysis.- 4.1. Translocations in Specific Locus Tests.- 4.2. Heritable Translocation Assays.- 4.3. Genetic Analysis of Reciprocal Translocations and Their Products.- 5. Detection and Study of Other Translocations and of Inversions.- 5.1. Robertsonian Translocations.- 5.2. Insertions.- 5.3. Inversions.- 6. Detection and Study of Deletions.- 6.1. X-Chromosomal Deletions.- 6.2. Autosomal Deletions.- 7. Conclusions.- 8. References.- 4 Cytogenetic Assays for Mitotic Poisons Using Somatic Animal Cells.- 1. Introduction.- 2. Mitotic Poisons and Their Genomic Effects.- 2.1. The Spindle Apparatus.- 2.2. The Centriole.- 2.3. Kinetochores.- 2.4. Cytokinesis.- 3. Assays with Diploid Mammalian Cells in Vitro.- 3.1. Choice of Cell Lines.- 3.2. Mitotic Arrest.- 3.3. Recovery Experiments.- 3.4. Aneuploidy Enumeration.- 3.5. Slide Reading.- 4. Assays with Bone Marrow Cells in Vivo.- 4.1. Animals.- 4.2. Techniques.- 5. Assays with Grasshopper Embryos.- 5.1. Test Materials.- 5.2. General Information about Grasshopper Embryos.- 5.3. Procedure.- 6. Conclusions.- 7. References.- 5 Detection of Aneuploidy in Drosophila.- 1. Introduction.- 1.1. Role of Drosophila.- 1.2. Definition of Aneuploidy.- 2. Issues.- 2.1. Sex.- 2.2. Germ Cell Stage.- 2.3. Other Factors.- 3. Assay Systems.- 3.1. Classical Test.- 3.2. Selective and Semi selective Tests.- 4. Known Positives.- 4.1. Colchicine.- 4.2. Methyl Mercury Hydroxide.- 4.3. Inhibitors of Nucleic Acid Synthesis.- 5. Summary.- 6. References.- 6 Mammalian Cytogenetic and Genetic Tests for Nondisjunction.- 1. Introduction.- 2. Cytogenetic Tests.- 2.1. Methods Using Primary and Secondary Gametocytes.- 2.2. Methods Using Spermatids and Spermatozoa.- 2.3. Methods Using Pre- and Postimplantation Embryos.- 3. Genetic Test Systems with the Mouse.- 3.1. The Numerical Sex-Chromosome Anomaly (NSA) Method.- 3.2. Tests Using Robertsonian Translocations.- 4. Summary and Conclusions.- 5. References.- 7 Using Repair-Deficient Chinese Hamster Ovary Cells to Study Mutagenesis.- 1. Introduction.- 2. Genetic and Biochemical Properties of Repair-Deficient Mutants.- 2.1. Complementation Groups of UV-Sensitive Mutants.- 2.2. Defective Excision Repair in UV-Sensitive Mutants.- 2.3. Defective Strand-Break Repair in Mutant EM9.- 2.4. Elevated Sister Chromatid Exchange in Mutant EM9.- 2.5. Complementation of CHO Mutations by Human Genes.- 3. Hypersensitivity of Repair Mutants to DNA-Damaging Agents.- 3.1. Sensitivity Determined by Colony Formation.- 3.2. Methodology for Measuring Mutations.- 3.3. Sensitivity to Mutation Induction.- 4. Rapid Detection of DNA-Damaging Agents by Differential Cytotoxicity (DC).- 4.1. Concept and Methodology of DC Assay.- 4.2. Response of Repair-Deficient Lines to Nonmutagens.- 4.3. Response of Repair-Deficient Lines to Monofunctional Bulky Mutagens.- 4.4. Response of Repair-Deficient Lines to Bifunctional Bulky Mutagens.- 4.5. Response of Mutants EM9 and UV-1 to Methylating and Ethylating Agents.- 4.6. Response of Mutant UV-1 to Various Other Agents.- 4.7. Response of DC Assay to Alkylation Congeners.- 4.8. DNA-Damaging Agents Not Detected by the DC Assay.- 4.9. Merits and Limitations of the DC Assay.- 5. Conclusions.- 6. References.- 8 Transplacental Genotoxic Agents: Cytogenetic Methods for Their Detection.- 1. Introduction.- 2. Animal Studies.- 2.1. Metaphase Analysis.- 2.2. Micronuclei.- 2.3. Sister Chromatid Exchange.- 2.4. Maternal-Fetal Comparisons.- 2.5. Cell and Tissue Specificity.- 2.6. Detection of Transplacental Carcinogens and Teratogens.- 2.7. General Comments on Animal Studies.- 3. Human Studies.- 3.1. Risk Factors in Childhood Cancers and Congenital Malformations.- 3.2. Choice of Cell Types and Assay Systems.- 3.3. Results of Population Monitoring.- 4. References.- 9 Computer Automation of Metaphase Finding, Sister Chromatid Exchange, and Chromosome Damage Analysis.- 1. Introduction.- 1.1. Value of Short-Term Cytogenetic Tests for Mutagenesis Testing.- 1.2. Need for High-Speed Automated Cytogenetic Analysis.- 2. Historical Trends in Computer Automation.- 2.1. Metaphase Finding and Karyotyping.- 2.2. Automated Chromosome Aberration and Sister Chromatid Exchange Scoring.- 3. Development of a System for Cytogenetic Mutagenicity Testing.- 3.1. Early Approaches.- 3.2. Image Analysis Configuration.- 3.3. Program Operation.- 4. Future Prospects for Full Automation.- 5. References.- 10 Mutagen-Sensitive Mutants and Chemical Mutagenesis in Drosaphila.- 1. Introduction.- 2. Isolation and Localization of Mutants.- 3. Biochemical Characteristics.- 3.1. Introduction.- 3.2. Photoreactivation.- 3.3. Excision Repair.- 3.4. Postreplication Repair.- 4. Larval Exposure.- 4.1. Spontaneous Mutations.- 4.2. Direct-Acting Mutagens.- 4.3. Promutagens.- 5. Adult Exposure.- 5.1. Spontaneous Mutations.- 5.2. Direct-Acting Mutagens.- 5.3. Promutagens.- 6. Maternal Effects.- 6.1. Spontaneous Mutations.- 6.2. Direct-Acting Mutagens.- 6.3. Promutagens.- 6.4. The Assay with st mus(3)302 Females.- 6.5. Statistics.- 7. Storage Effect.- 8. Conclusions.- 9. References.- 11 Chromosomal Causes for Fertility Reduction in Mammals.- 1. Introduction.- 2. Numerical Chromosome Mutations of the Sex Chromosomes and Related Conditions.- 2.1. Sex-Chromosome Anomalies in the Male.- 2.2. Sex-Chromosome Anomalies in the Female.- 3. Structural Chromosome Anomalies.- 3.1. Reciprocal Translocations between the Autosomes.- 3.2. Robertsonian Translocations.- 3.3. Inversions.- 3.4. Duplications and Deficiencies.- 4. Combinations of Chromosome Mutants within One Carrier.- 4.1. Two Reciprocal Translocations That Have No Chromosomes in Common.- 4.2. Two Reciprocal Translocations That Have One Chromosome in Common.- 4.3. Two Reciprocal Translocations That Have Two Chromosomes in Common.- 4.4. Combinations of Robertsonian Translocations That Have No Arms in Common.- 4.5. Combinations of Two Robertsonian Translocations That Have One Chromosome in Common.- 4.6. Combinations of Robertsonian and Reciprocal Translocations.- 4.7. The Combination of Two Paracentric Inversions within the Same Chromosome.- 5. Viable Unbalanced Progeny Obtained from Translocation Heterozygote Females and Males.- 6. Why is Chromosomal Infertility More Clearly Expressed in the Male Than in the Female? Consideration of X-Autosome Translocations.- 7. References.- 12 Mutagenesis and Plasmids.- 1. Introduction.- 2. Historical Overview of Plasmids.- 2.1. Colicin Plasmids.- 2.2. Resistance Transfer Plasmids (R Plasmids).- 2.3. Plasmid Compatibility.- 2.4. Plasmid Replication.- 2.5. Plasmid Size.- 2.6. DNA Damage and Plasmids.- 2.7. Spontaneous Mutagenesis and Plasmids.- 3. Survey of Thirty-Three R Plasmids.- 3.1. Materials and Methods.- 3.2. Results.- 3.3. Discussion.- 4. Mechanisms of Plasmid-Mediated Effects on Mutagenesis and Survival.- 4.1. Genetic Studies.- 4.2. Biochemical Studies.- 4.3. Molecular Studies.- 4.4. One versus Several Mechanisms.- 5. References.- 13 Mutation in Somatic Cells as Determined by Electrophoretic Analysis of Mutagen-Exposed Chinese Hamster Ovary Cells.- 1. Introduction.- 1.1. Characterization of Electrophoretic Mutations in Natural Populations.- 1.2. Rationale for Isolation of Electrophoretically Detectable Mutations.- 2. Methods of Procedure.- 2.1. Isolation of Clones Exposed to Mutagens.- 2.2. Electrophoretic Detection of Mutations at Enzyme Loci.- 2.3. Mutant Criteria.- 3. Results and Discussion.- 3.1. Loci at Which Mutations Were Obtained.- 3.2. Functional Ploidy in CHO Cells and Its Effect on Mutation Frequency.- 3.3. Mutation Frequency in Mammalian Somatic Cells.- 4. Summary.- 5. References.