Table of Contents

Preface xxix List of Contributors xxxi Section 1 Introduction 1 1 Molecular and Biochemical Toxicology: Definition and Scope 3 Ernest Hodgson and Robert C. Smart 1.1 Introduction 3 1.2 Sources of Information 5 1.3 Toxicology 5 1.4 Molecular and Cellular Toxicology 6 1.5 Proteomics and Metabolomics 8 1.6 Role of Molecular, Cellular, and Biochemical Toxicology: Implications for Risk Assessment 8 1.7 Conclusions 9 Suggested Reading 9 Section 2 Techniques in Biochemical and Molecular Toxicology 11 2 Molecular Techniques for the Study of Gene Function 13 Yoshiaki Tsuji and Robert C. Smart 2.1 Applicability of Molecular Techniques to Toxicology 13 2.2 Overview of Genes, Chromatin, and Their Relationship 15 2.3 Approaches to Characterize the Functions of Genes 20 2.4 Gene Targeting Technologies 31 2.5 Analysis of Gene Expression and Regulatory Mechanisms 35 2.6 Methods to Evaluate Gene Function in an Animal Model 45 References 54 Suggested Reading 54 3 Transcriptomics 55 B. Alex Merrick 3.1 Introduction 55 3.2 Cellular Organization and the Transcriptome 58 3.3 RNA Isolation 62 3.4 Platforms for Transcriptome Analysis: Microarrays 64 3.5 RNA ]seq: NextGen Sequencing of the Transcriptome 72 3.6 Validation of Transcriptome Analysis 81 3.7 Analysis of Gene Expression Data 82 3.8 Summary 86 References 87 4 Proteomics 91 Michael S. Bereman 4.1 Introduction to Proteomics 91 4.2 Mass Spectrometry 94 4.3 Quantitation of Proteins by LC ]MS/MS 107 4.4 Emerging Research Areas in Proteomics 109 4.5 Summary 112 Suggested Reading 112 5 Metabolomics 115 Susan C. J. Sumner, Wimal Pathmasiri, James E. Carlson, Susan L. McRitchie, and Timothy R. Fennell 5.1 Introduction 115 5.2 Endogenous and Exogenous Metabolites 116 5.3 Study Design and Experimental Considerations 117 5.4 Applications of Metabolomics 120 5.5 Technologies for Targeted and Broad ]Spectrum Metabolomics 122 5.6 Statistical and Multivariate Analysis and Pathway Mapping 127 5.7 Summary 130 Acknowledgment 130 References 131 6 Cellular Techniques 135 Sharon A. Meyer and Barbara A. Wetmore 6.1 Introduction 135 6.2 Cellular Studies in Intact Tissue 137 6.3 Studies 6.4 Monolayer Cell Culture 142 6.5 Observation of Cultured Cells 148 6.6 Indicators of Toxicity 149 6.7 Important Considerations and Advances 152 6.8 Replacement of Animal Testing with Cell Culture Models 155 6.9 Conclusion 157 Suggested Reading 157 Journals 158 7 Basic Concepts of Molecular Epidemiological Research Methods 159 Cathrine Hoyo, David A. Skaar, and Randy L. Jirtle 7.1 Introduction 159 7.2 Molecular Epidemiology 160 7.3 Descriptive Epidemiologic Study Designs 164 7.4 Analytic Epidemiologic Studies 167 7.5 Experimental Studies 173 7.6 Inferring Causality from Molecular Epidemiologic Data 174 7.7 Summary 182 References 183 Suggested Reading 184 Reading Materials Related to Examples 184 Section 3 Mechanisms in Molecular and Biochemical Toxicology 187 8 Phase I and Phase II Metabolism and Metabolic Interactions: A Summary 189 Ernest Hodgson 8.1 Introduction 189 8.2 Metabolic Enzymes 189 8.3 Phase I Reactions 191 8.4 Phase II Reactions 196 8.5 Reactive Metabolites 199 8.6 Factors Affecting Metabolism 200 8.7 Synergism and Potentiation 204 8.8 Biphasic Effects 204 8.9 Environmental Effects 204 8.10 Human Variation in Toxicant Metabolism 204 8.11 Summary of Toxicant Metabolism 205 Suggested Reading 206 9 Structure, Mechanism, and Regulation of Cytochromes P450 209 John M. Seubert, Matthew L. Edin, and Darryl C. Zeldin 9.1 Introduction 209 9.2 Complexity of the Cytochrome 450 Gene Superfamily 210 9.3 Cytochrome P450 Structure 214 9.4 Mechanisms of P450 Catalysis 217 9.5 Cytochrome P450 Regulation 225 9.6 Transgenic Animal Models 235 9.7 Reactive Oxygen Species 235 9.8 Posttranslational Modification of P450s 236 9.9 Summary 237 Suggested Reading 238 10 Polymorphisms in Phase I and Phase II Genes and Outcomes 239 Yoshiaki Tsuji, Edward L. Croom, and Ernest Hodgson 10.1 Introduction 239 10.2 Toxicogenetics and Single Nucleotide Polymorphisms (SNPS) 240 10.3 Polymorphic Cytochrome P450 and Xenobiotics Metabolism 242 10.4 Other Polymorphic Phase I Genes and Xenobiotics Metabolism 248 10.5 Polymorphisms: Mechanistic Classification 251 10.6 Methods for the Study of Polymorphisms 252 10.7 Phase II Gene Polymorphisms and Xenobiotics Metabolism 253 10.8 Regulation of Phase II Genes Via Antioxidant Responsive Element 267 Suggested Reading 271 11 Cellular Transport and Elimination 273 David S. Miller and Ronald E. Cannon 11.1 Transport as a Determinant of Xenobiotic Action 273 11.2 Factors Affecting Membrane/Tissue Permeability 274 11.3 Xenobiotic Transporters 279 11.4 Altered Xenobiotic Transport 285 Suggested Reading 290 12 Nuclear Receptors 293 Seth W. Kullman, William S. Baldwin, and Gerald A. LeBlanc 12.1 Introduction 293 12.2 NR Structure Function 294 12.3 Nomenclature 296 12.4 NR Transactivation 297 12.5 NRS in Toxicology 306 12.6 Endobiotic and Xenobiotic Metabolism 319 12.7 Defining New NR Targets for Toxicity: Toxcast and Tox21 323 Reference 326 Suggested Reading 326 13 Mechanisms of Cell Death 327 Mac Law and Susan Elmore 13.1 Introduction 327 13.2 How Cells/Tissues React to "Stress" 328 13.3 Cell Injury and Cell Death 330 13.4 Morphology of Cell Injury and Cell Death 339 13.5 Apoptosis, Morphology, and Mechanisms 342 13.6 Other Cell Death Modalities 364 Acknowledgments 369 Reference 369 Suggested Reading 369 14 Mitochondrial Dysfunction 371 Jun Ninomiya ]Tsuji 14.1 Introduction 371 14.2 Mitochondrial Function 372 14.3 Mitochondrial Apoptosis/Necrosis 378 14.4 Toxicant ]Induced Mitochondrial Apoptosis/Necrosis 387 References 389 15 Reactive Metabolites, Reactive Oxygen Species (ROS), and Toxicity 391 Elizabeth L. Mackenzie and Yoshiaki Tsuji 15.1 Introduction 391 15.2 Enzymes Involved in Bioactivation 394 15.3 Stability of Reactive Metabolites 403 15.4 Factors Affecting Metabolic Balance and Toxicity 405 15.5 Reactive Oxygen Species (ROS) and Toxicity 409 Suggested Reading 419 16 DNA Damage and Mutagenesis 421 Zhigang Wang 16.1 Introduction 421 16.2 Endogenous DNA Damage 422 16.3 Environmental DNA Damage 435 16.4 Concepts of Mutagenesis 453 16.5 Mechanisms of DNA Damage ]Induced Mutagenesis 456 Suggested Reading 482 17 DNA Repair 485 Isabel Mellon 17.1 Introduction 485 17.2 Direct Reversal of Base Damage 487 17.3 Base Excision Repair 495 17.4 Nucleotide Excision Repair 505 17.5 Mismatch Repair 516 17.6 Recombinational Repair 522 17.7 DNA Repair and Chromatin Structure 528 17.8 DNA Repair in Mitochondria 531 17.9 DNA Repair and Cancer 532 17.10 Summary 533 Reference 533 Suggested Reading 533 18 Carcinogenesis 535 Robert C. Smart and Jonathan R. Hall 18.1 Introduction 535 18.2 Human Cancer 537 18.3 Categorization of Agents Associated with Carcinogenesis 551 18.4 Somatic Mutation Theory 553 18.5 Epigenetic Mechanism of Tumorigenesis 559 18.6 Multistage Tumorigenesis 560 18.7 Oncogenes 565 18.8 Tumor Suppressor Genes 578 18.9 Mutator Phenotype/DNA Stability Genes 586 18.10 Conclusions 587 Reference 588 Suggested Reading 588 Section 4 Molecular and Biochemical Aspects of Organ Toxicology 589 19 Molecular Mechanisms of Respiratory Toxicity 591 James C. Bonner 19.1 Introduction 591 19.2 Anatomy and Function of the Respiratory Tract 591 19.3 Toxicant ]Induced Lung Injury, Remodeling, and Repair 603 19.4 Occupational and Environmental Lung Diseases 617 Suggested Reading 627 20 Molecular Mechanisms of Hepatotoxicity 629 Supriya R. Kulkarni, Andrew D. Wallace, Sharon A. Meyer, and Angela L. Slitt 20.1 Introduction 629 20.2 Liver Organization and Cellular Components 630 20.3 Acute and Chronic Hepatotoxicity 635 20.4 Types of Hepatotoxicity 637 20.5 Mechanisms of Hepatotoxicity 643 20.6 Autoprotection and Protective Priming 654 20.7 Experimental Prediction of Hepatotoxicity 655 20.8 Compounds Causing Liver Injury 657 20.9 Conclusions 661 Suggested Reading 661 21 Molecular Mechanisms of Renal Toxicology 665 Lawrence H. Lash 21.1 Introduction 665 21.2 Influence of Renal Structure and Function on Susceptibility to Nephrotoxicity and Renal Damage 667 21.3 Classification of Renal Injury 682 21.4 Assessment of Renal Function in the Clinic and in Animal Models 684 21.5 General Considerations for Choosing an Experimental Model to Study Nephrotoxicity 686 21.6 In Vitro Models to Study Mechanisms of Renal Injury 689 21.7 General Considerations Regarding Responses to Toxicants at the Cellular Level 695 21.8 Mechanisms of Toxicant Action in the Kidneys 697 21.9 Human Disease and Risk Assessment in Renal Toxicology 702 21.10 Summary 703 References 704 22 Molecular Mechanisms of Neurotoxicity 709 Kimberly P. Keil, Marianna Stamou, and Pamela J. Lein 22.1 Introduction 709 22.2 Neurotransmission 715 22.3 Inter ] and Intracellular Signaling 724 22.4 Excitotoxicity 736 22.5 Protein Modifications 742 22.6 Neuroinflammation 747 22.7 Epigenetics 758 22.8 Concluding Remarks 767 Suggested Reading 769 23 Molecular Mechanisms of Immunotoxicity 773 Tai L. Guo, Joella Xu, Yingjia Chen, Daniel E. Lefever, Guannan Huang, and David A. Lawrence 23.1 Introduction and Overview of the Immune System 773 23.2 Immune Hypersensitivities and Autoimmune Disease 788 23.3 Mucosal Immunity, the Microbiome, and Food Allergies 791 23.4 Molecular Immunotoxicology of Environmental Stressors 801 23.5 Methods for Assessing Immunotoxicology 815 23.6 Summary 817 References 817 24 Molecular Mechanisms of Reproductive Toxicity 823 Ayelet Ziv ]Gal, Catheryne Chiang, and Jodi Anne Flaws 24.1 Introduction 823 24.2 Organization of the Reproductive System: Sexual Differentiation 825 24.3 Neuroendocrine Regulation of Reproduction 826 24.4 Female Reproductive System 829 24.5 Toxicity in the Male Reproductive System 840 24.6 Transgenerational Effects on Reproduction 845 24.7 Summary 846 References 847 25 Molecular Mechanisms of Developmental Toxicity 851 Antonio Planchart 25.1 Introduction 851 25.2 Overview of Development and General Principles 852 25.3 Wilson's Principles of Teratology 859 25.4 Selected Examples of Developmental Toxicants 868 25.5 Advances in Developmental Toxicology Methods 873 25.6 Summary 875 References 875 Section 5 Emerging Areas in Molecular and Biochemical Toxicology 877 26 Computational and Molecular Approaches to Risk Assessment 879 Richard S. Judson, John Wambaugh, Kristin Isaacs, and Russell S. Thomas 26.1 Introduction 879 26.2 High ]Throughput Bioactivity 883 26.3 High ]Throughput Toxicokinetics 889 26.4 High ]Throughput Exposure 897 26.5 Summary 905 References 906 27 Nanotoxicology 909 James C. Bonner 27.1 Introduction 909 27.2 Naturally Occurring and Unintentional Nanoparticles 913 27.3 Engineered Nanomaterials 913 27.4 Exposure to Nanoparticles 915 27.5 Protein Corona Formation on Nanoparticles 918 27.6 Nanoparticle Interactions with Biological Barriers 920 27.7 Degradation and Clearance 921 27.8 Adverse Effects of Nanoparticles 923 27.9 Nanomedicine 929 27.10 Life Cycle of Nanoparticles in the Environment 931 Suggested Reading 931 28 Developmental Origins of Health and Disease 933 Michael Cowley 28.1 Introduction 933 28.2 Historical Perspective: Birth Weight and Early Life Nutrition in Adult Health 934 28.3 The Effects of Environmental Chemicals on the Programming of Adult Health 935 28.4 Biological Mechanisms 938 28.5 Conclusions 943 Suggested Reading 943 29 Exposome 945 Stephen M. Rappaport 29.1 Introduction 945 29.2 The Exposome and Disease Pathways 949 29.3 The Blood Exposome 951 29.4 The Exposome and Social Factors 957 29.5 Discovering Causes of Disease 958 29.6 The Future of the Exposome 961 Acknowledgments 962 References 963 Index 969

About the Author

ROBERT C. SMART, PhD, is a William Neal Reynolds Professor of Toxicology, the Director of the Center for Human Health and the Environment, and the former Director of the Toxicology Graduate Program at North Carolina State University. Together with Dr. Hodgson, he coedited the two previous editions of this book. ERNEST HODGSON, PhD, is Distinguished Professor Emeritus of Environmental and Molecular Toxicology and Executive Director of the Foundation for Agromedicine and Toxicology at North Carolina State University. Alongside the previous editions of this book, he edited four editions of A Textbook of Modern Toxicology (Wiley) and is the Editor of the Journal of Biochemical and Molecular Toxicology.