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
