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Dieses Lehrbuch für fortgeschrittene Studenten der Fachrichtung Toxikologie ist weit mehr als eine Einführung in das Fachgebiet. Es bietet detaillierte Informationen zu den zugrunde liegenden Mechanismen, mit denen Giftstoffe ihre Negativwirkungen entfalten.- Verbindet die traditionelle Toxikologie mit modernen Molekularverfahren, wichtig für Lehrveranstaltungen höherer Semester und für Fachstudiengänge.- Nutzt einen didaktischen Ansatz und vermittelt Grundlagen der Biologie sowie theoretisches Hintergrundwissen zur Darstellung der Methodiken.- Verbindet umfassend verschiedenste dynamische Aspekte der biochemischen und molekularen Toxikologie.- Unterstützt Studenten und Toxikologen beim Verständnis einer Vielzahl von Problemstellungen und Themen, die von einer Gruppe von Experten mit unterschiedlichster Ausrichtung zusammengestellt wurden.- Eine gute Einführung in die biochemische Toxikologie organischer Substanzen und der relevanten Methodiken im Detail ? Ein empfehlenswertes Lehrbuch für die Zielgruppe mit gutem Preis-Leistungs-Verhältnis ? Rezension der 4. Auflage im BTS Newsletter

Molecular and Biochemical Toxicology

Preface xxixList of Contributors xxxiSection 1 Introduction 11 Molecular and Biochemical Toxicology: Definition and Scope 3Ernest Hodgson and Robert C. Smart1.1 Introduction 31.2 Sources of Information 51.3 Toxicology 51.4 Molecular and Cellular Toxicology 61.5 Proteomics and Metabolomics 81.6 Role of Molecular, Cellular, and Biochemical Toxicology: Implications for Risk Assessment 81.7 Conclusions 9Suggested Reading 9Section 2 Techniques in Biochemical and Molecular Toxicology 112 Molecular Techniques for the Study of Gene Function 13Yoshiaki Tsuji and Robert C. Smart2.1 Applicability of Molecular Techniques to Toxicology 132.2 Overview of Genes, Chromatin, and Their Relationship 152.3 Approaches to Characterize the Functions of Genes 202.4 Gene Targeting Technologies 312.5 Analysis of Gene Expression and Regulatory Mechanisms 352.6 Methods to Evaluate Gene Function in an Animal Model 45References 54Suggested Reading 543 Transcriptomics 55B. Alex Merrick3.1 Introduction 553.2 Cellular Organization and the Transcriptome 583.3 RNA Isolation 623.4 Platforms for Transcriptome Analysis: Microarrays 643.5 RNA?]seq: NextGen Sequencing of the Transcriptome 723.6 Validation of Transcriptome Analysis 813.7 Analysis of Gene Expression Data 823.8 Summary 86References 874 Proteomics 91Michael S. Bereman4.1 Introduction to Proteomics 914.2 Mass Spectrometry 944.3 Quantitation of Proteins by LC?]MS/MS 1074.4 Emerging Research Areas in Proteomics 1094.5 Summary 112SuggestedReading 1125 Metabolomics 115Susan C. J. Sumner, Wimal Pathmasiri, James E. Carlson, Susan L. McRitchie, and Timothy R. Fennell5.1 Introduction 1155.2 Endogenous and Exogenous Metabolites 1165.3 Study Design and Experimental Considerations 1175.4 Applications of Metabolomics 1205.5 Technologies for Targeted and Broad?]Spectrum Metabolomics 1225.6 Statistical and Multivariate Analysis and Pathway Mapping 1275.7 Summary 130Acknowledgment 130References 1316 Cellular Techniques 135Sharon A. Meyer and Barbara A. Wetmore6.1 Introduction 1356.2 Cellular Studies in Intact Tissue 1376.3 Studies6.4 Monolayer Cell Culture 1426.5 Observation of Cultured Cells 1486.6 Indicators of Toxicity 1496.7 Important Considerations and Advances 1526.8 Replacement of Animal Testing with Cell Culture Models 1556.9 Conclusion 157Suggested Reading 157Journals 1587 Basic Concepts of Molecular Epidemiological Research Methods 159Cathrine Hoyo, David A. Skaar, and Randy L. Jirtle7.1 Introduction 1597.2 Molecular Epidemiology 1607.3 Descriptive Epidemiologic Study Designs 1647.4 Analytic Epidemiologic Studies 1677.5 Experimental Studies 1737.6 Inferring Causality from Molecular Epidemiologic Data 1747.7 Summary 182References 183Suggested Reading 184Reading Materials Related to Examples 184Section 3 Mechanisms in Molecular and Biochemical Toxicology 1878 Phase I and Phase II Metabolism and Metabolic Interactions: A Summary 189Ernest Hodgson8.1 Introduction 1898.2 Metabolic Enzymes 1898.3 Phase I Reactions 1918.4 Phase II Reactions 1968.5 Reactive Metabolites 1998.6 Factors Affecting Metabolism 2008.7 Synergism and Potentiation 2048.8 Biphasic Effects 2048.9 Environmental Effects 2048.10 Human Variation in Toxicant Metabolism 2048.11 Summary of Toxicant Metabolism 205SuggestedReading 2069 Structure, Mechanism, and Regulation of Cytochromes P450 209John M. Seubert, Matthew L. Edin, and Darryl C. Zeldin9.1 Introduction 2099.2 Complexity of the Cytochrome 450 Gene Superfamily 2109.3 Cytochrome P450 Structure 2149.4 Mechanisms of P450 Catalysis 2179.5 Cytochrome P450 Regulation 2259.6 Transgenic Animal Models 2359.7 Reactive Oxygen Species 2359.8 Posttranslational Modification of P450s 2369.9 Summary 237SuggestedReading 23810 Polymorphisms in Phase I and Phase II Genes and Outcomes 239Yoshiaki Tsuji, Edward L. Croom, and Ernest Hodgson10.1 Introduction 23910.2 Toxicogenetics and Single Nucleotide Polymorphisms (SNPS) 24010.3 Polymorphic Cytochrome P450 and Xenobiotics Metabolism 24210.4 Other Polymorphic Phase I Genes and Xenobiotics Metabolism 24810.5 Polymorphisms: Mechanistic Classification 25110.6 Methods for the Study of Polymorphisms 25210.7 Phase II Gene Polymorphisms and Xenobiotics Metabolism 25310.8 Regulation of Phase II Genes Via Antioxidant Responsive Element 267SuggestedReading 27111 Cellular Transport and Elimination 273David S. Miller and Ronald E. Cannon11.1 Transport as a Determinant of Xenobiotic Action 27311.2 Factors Affecting Membrane/Tissue Permeability 27411.3 Xenobiotic Transporters 27911.4 Altered Xenobiotic Transport 285SuggestedReading 29012 Nuclear Receptors 293Seth W. Kullman, William S. Baldwin, and Gerald A. LeBlanc12.1 Introduction 29312.2 NR Structure Function 29412.3 Nomenclature 29612.4 NR Transactivation 29712.5 NRS in Toxicology 30612.6 Endobiotic and Xenobiotic Metabolism 31912.7 Defining New NR Targets for Toxicity: Toxcast and Tox21 323Reference 326Suggested Reading 32613 Mechanisms of Cell Death 327Mac Law and Susan Elmore13.1 Introduction 32713.2 How Cells/Tissues React to "Stress" 32813.3 Cell Injury and Cell Death 33013.4 Morphology of Cell Injury and Cell Death 33913.5 Apoptosis, Morphology, and Mechanisms 34213.6 Other Cell Death Modalities 364Acknowledgments 369Reference 369Suggested Reading 36914 Mitochondrial Dysfunction 371Jun Ninomiya?]Tsuji14.1 Introduction 37114.2 Mitochondrial Function 37214.3 Mitochondrial Apoptosis/Necrosis 37814.4 Toxicant?]Induced Mitochondrial Apoptosis/Necrosis 387References 38915 Reactive Metabolites, Reactive Oxygen Species (ROS), and Toxicity 391Elizabeth L. Mackenzie and Yoshiaki Tsuji15.1 Introduction 39115.2 Enzymes Involved in Bioactivation 39415.3 Stability of Reactive Metabolites 40315.4 Factors Affecting Metabolic Balance and Toxicity 40515.5 Reactive Oxygen Species (ROS) and Toxicity 409SuggestedReading 41916 DNA Damage and Mutagenesis 421Zhigang Wang16.1 Introduction 42116.2 Endogenous DNA Damage 42216.3 Environmental DNA Damage 43516.4 Concepts of Mutagenesis 45316.5 Mechanisms of DNA Damage?]Induced Mutagenesis 456SuggestedReading 48217 DNA Repair 485Isabel Mellon17.1 Introduction 48517.2 Direct Reversal of Base Damage 48717.3 Base Excision Repair 49517.4 Nucleotide Excision Repair 50517.5 Mismatch Repair 51617.6 Recombinational Repair 52217.7 DNA Repair and Chromatin Structure 52817.8 DNA Repair in Mitochondria 53117.9 DNA Repair and Cancer 53217.10 Summary 533Reference 533Suggested Reading 53318 Carcinogenesis 535Robert C. Smart and Jonathan R. Hall18.1 Introduction 53518.2 Human Cancer 53718.3 Categorization of Agents Associated with Carcinogenesis 55118.4 Somatic Mutation Theory 55318.5 Epigenetic Mechanism of Tumorigenesis 55918.6 Multistage Tumorigenesis 56018.7 Oncogenes 56518.8 Tumor Suppressor Genes 57818.9 Mutator Phenotype/DNA Stability Genes 58618.10 Conclusions 587Reference 588Suggested Reading 588Section 4 Molecular and Biochemical Aspects of Organ Toxicology 58919 Molecular Mechanisms of Respiratory Toxicity 591James C. Bonner19.1 Introduction 59119.2 Anatomy and Function of the Respiratory Tract 59119.3 Toxicant?]Induced Lung Injury, Remodeling, and Repair 60319.4 Occupational and Environmental Lung Diseases 617SuggestedReading 62720 Molecular Mechanisms of Hepatotoxicity 629Supriya R. Kulkarni, Andrew D. Wallace, Sharon A. Meyer, and Angela L. Slitt20.1 Introduction 62920.2 Liver Organization and Cellular Components 63020.3 Acute and Chronic Hepatotoxicity 63520.4 Types of Hepatotoxicity 63720.5 Mechanisms of Hepatotoxicity 64320.6 Autoprotection and Protective Priming 65420.7 Experimental Prediction of Hepatotoxicity 65520.8 Compounds Causing Liver Injury 65720.9 Conclusions 661SuggestedReading 66121 Molecular Mechanisms of Renal Toxicology 665Lawrence H. Lash21.1 Introduction 66521.2 Influence of Renal Structure and Function on Susceptibility to Nephrotoxicity and Renal Damage 66721.3 Classification of Renal Injury 68221.4 Assessment of Renal Function in the Clinic and in Animal Models 68421.5 General Considerations for Choosing an Experimental Model to Study Nephrotoxicity 68621.6 In Vitro Models to Study Mechanisms of Renal Injury 68921.7 General Considerations Regarding Responses to Toxicants at the Cellular Level 69521.8 Mechanisms of Toxicant Action in the Kidneys 69721.9 Human Disease and Risk Assessment in Renal Toxicology 70221.10 Summary 703References 70422 Molecular Mechanisms of Neurotoxicity 709Kimberly P. Keil, Marianna Stamou, and Pamela J. Lein22.1 Introduction 70922.2 Neurotransmission 71522.3 Inter?] and Intracellular Signaling 72422.4 Excitotoxicity 73622.5 Protein Modifications 74222.6 Neuroinflammation 74722.7 Epigenetics 75822.8 Concluding Remarks 767SuggestedReading 76923 Molecular Mechanisms of Immunotoxicity 773Tai L. Guo, Joella Xu, Yingjia Chen, Daniel E. Lefever, Guannan Huang, and David A. Lawrence23.1 Introduction and Overview of the Immune System 77323.2 Immune Hypersensitivities and Autoimmune Disease 78823.3 Mucosal Immunity, the Microbiome, and Food Allergies 79123.4 Molecular Immunotoxicology of Environmental Stressors 80123.5 Methods for Assessing Immunotoxicology 81523.6 Summary 817References 81724 Molecular Mechanisms of Reproductive Toxicity 823Ayelet Ziv?]Gal, Catheryne Chiang, and Jodi Anne Flaws24.1 Introduction 82324.2 Organization of the Reproductive System: Sexual Differentiation 82524.3 Neuroendocrine Regulation of Reproduction 82624.4 Female Reproductive System 82924.5 Toxicity in the Male Reproductive System 84024.6 Transgenerational Effects on Reproduction 84524.7 Summary 846References 84725 Molecular Mechanisms of Developmental Toxicity 851Antonio Planchart25.1 Introduction 85125.2 Overview of Development and General Principles 85225.3 Wilson's Principles of Teratology 85925.4 Selected Examples of Developmental Toxicants 86825.5 Advances in Developmental Toxicology Methods 87325.6 Summary 875References 875Section 5 Emerging Areas in Molecular and Biochemical Toxicology 87726 Computational and Molecular Approaches to Risk Assessment 879Richard S. Judson, John Wambaugh, Kristin Isaacs, and Russell S. Thomas26.1 Introduction 87926.2 High?]Throughput Bioactivity 88326.3 High?]Throughput Toxicokinetics 88926.4 High?]Throughput Exposure 89726.5 Summary 905References 90627 Nanotoxicology 909James C. Bonner27.1 Introduction 90927.2 Naturally Occurring and Unintentional Nanoparticles 91327.3 Engineered Nanomaterials 91327.4 Exposure to Nanoparticles 91527.5 Protein Corona Formation on Nanoparticles 91827.6 Nanoparticle Interactions with Biological Barriers 92027.7 Degradation and Clearance 92127.8 Adverse Effects of Nanoparticles 92327.9 Nanomedicine 92927.10 Life Cycle of Nanoparticles in the Environment 931Suggested Reading 93128 Developmental Origins of Health and Disease 933Michael Cowley28.1 Introduction 93328.2 Historical Perspective: Birth Weight and Early Life Nutrition in Adult Health 93428.3 The Effects of Environmental Chemicals on the Programming of Adult Health 93528.4 Biological Mechanisms 93828.5 Conclusions 943SuggestedReading 94329 Exposome 945Stephen M. Rappaport29.1 Introduction 94529.2 The Exposome and Disease Pathways 94929.3 The Blood Exposome 95129.4 The Exposome and Social Factors 95729.5 Discovering Causes of Disease 95829.6 The Future of the Exposome 961Acknowledgments 962References 963Index 969