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Molecular and Biochemical Toxicology, 5th Edition

Robert C. Smart (Editor), Ernest Hodgson (Editor)
ISBN: 978-1-119-04241-9
1040 pages
December 2017
Molecular and Biochemical Toxicology, 5th Edition (1119042410) cover image

Description

Written as an advanced text for toxicology students, this book is much more than an introduction and provides in-depth information describing the underlying mechanisms through which toxicants produce their adverse responses.

•    Links traditional toxicology to modern molecular techniques, important for teaching to graduate courses and professional studies
•    Uses a didactic approach with basic biological or theoretical background for the methodology presented
•    Brings together and comprehensively covers a range of dynamic aspects in biochemical and molecular toxicology
•    Guides student and professional toxicologists in comprehending a broad range of issues, compiled and authored by a diverse group of experts
•    “A good introductory textbook covering the biochemical toxicology of organic substances and the relevant methodology in some detail.... It offers good value for money and can be recommended as a textbook for appropriate courses” – BTS Newsletter review of the 4th edition
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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

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Author Information

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.

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