Molecular and biochemical toxicology

MOLECULAR AND BIOCHEMICAL TOXICOLOGY......Page 4
CONTENTS......Page 8
Preface......Page 34
Contributors......Page 36
1.1 Introduction......Page 40
1.3 Biochemical Toxicology......Page 41
1.5 Molecular Toxicology......Page 42
Suggested Reading......Page 43
2.1 Applicability of Molecular Techniques to Toxicology......Page 44
2.2 Overview of the Genetic Code and Flow of Genetic Information......Page 45
2.3 Molecular Cloning......Page 47
2.3.2 Identification of Bacterial Colonies that Contain Recombinant DNA......Page 48
2.3.3 Construction of cDNA Library......Page 50
2.4 Southern and Northern Blot Analyses......Page 52
2.5 Polymerase Chain Reaction (PCR)......Page 53
2.6.2 Nuclear Run-On......Page 54
2.6.4 Microarrays......Page 55
2.6.5 Reverse Transcriptase-PCR (RT-PCR) and Real-Time PCR......Page 56
2.7.1 Eukaryotic Expression Systems......Page 57
2.7.2a Procedure for Making Transgenic Mice Using Zygote Injection......Page 59
2.7.2b Procedure for Making Knockout Mice Using Embryonic Stem Cells......Page 60
2.7.2d Cre-loxP Recombination System......Page 61
Suggested Reading......Page 62
3.1 Introduction......Page 64
3.2 A Primer of Genomics......Page 65
3.3 Tools and Approaches......Page 68
3.4 Genomes......Page 69
3.5.1 Microarrays......Page 70
3.5.1a Wet and Dry Lab Procedures......Page 72
3.5.2 DNA Arrays......Page 76
3.6 Conclusions......Page 77
Suggested Reading......Page 78
4.1.1 Attributes of Proteins......Page 80
4.1.2 History of Proteomics......Page 81
4.2.2 Mass and Charge......Page 83
4.4 Mass Spectrometers and Protein Identification......Page 85
4.4.2 MALDI-TOF and Peptide Fingerprints......Page 86
4.4.3 ESI-MS/MS, LC-MS/MS, and Sequence Tags......Page 88
4.4.4 Mass Spectrometers: Three Components......Page 89
4.4.5 Mass Analyzers......Page 90
4.5.1 Two-Dimensional Gel Separation or DIGE and Mass Spectrometry......Page 91
4.5.2 MudPIT......Page 93
4.5.3 ICAT, SILAC, iTRAQ......Page 95
4.5.4 Retentate Chromatography Mass Spectrometry (RC-MS)......Page 98
4.5.5 Antibody Arrays......Page 101
4.5.6 Advantages and Disadvantages of Proteomic Platforms......Page 103
4.7 Summary......Page 104
Suggested Reading......Page 105
5.1.1 Definitions......Page 106
5.1.2 Nonbiased Approaches in Metabolomics......Page 107
5.2 Methods......Page 108
5.2.1a Ionization......Page 109
5.2.2a Theory......Page 110
5.2.2b The NMR Spectrum......Page 112
5.2.3 NMR and Metabolomics......Page 113
5.3.1 Metabolomics in Diagnostics......Page 114
5.4 Metabolomics and Toxicology......Page 115
5.4.1 Attrition Rates of Drugs......Page 116
Suggested Reading......Page 117
6.1.1 Introduction to Biological Sequence Analysis......Page 120
6.2 Obtaining the Genbank Record of a Known Gene......Page 121
6.3.1 Homology......Page 123
6.3.2 Pairwise Sequence Alignment......Page 124
6.3.3 Evaluating Sequence Alignments......Page 126
6.3.4 Finding the Optimal Alignment......Page 127
6.3.5 Local and Global Alignment......Page 128
6.4 Database Searching with BLAST......Page 129
6.4.1 The BLAST Algorithm......Page 130
6.4.2 BLAST Statistics......Page 131
6.4.3 A BLAST Example......Page 132
6.5.1 Regular Expressions......Page 134
6.5.2 Position-Specific Scoring Matrices......Page 135
6.6.1 Background Principles......Page 136
6.6.1b Genetic Markers......Page 137
6.6.2a Human Pedigrees......Page 138
6.6.2b Inbred Line Crosses......Page 139
6.6.3 Association Mapping......Page 140
6.6.3a Linkage Disequilbrium......Page 141
6.6.3c Case–Control Tests......Page 142
6.6.4 Environmental Factors in Gene Mapping......Page 143
Suggested Reading......Page 145
7.2 Definitions......Page 148
7.3 Immunogens and Antigens......Page 149
7.4.1a Immunogen Preparation......Page 150
7.4.1b Immunization......Page 151
7.4.1c Serum Collection and Screening for Antibody Titer......Page 152
7.5.1 Monoclonal Antibody Production......Page 153
7.6.1 Immunohistochemistry......Page 155
7.6.3 Immunoprecipitation......Page 156
7.6.4 Immunoblotting (Western Blotting)......Page 158
7.6.5 Radioimmunoassay......Page 159
7.6.6 Enzyme-Linked Immunosorbant Assay......Page 161
7.6.8 Detection of Toxicant–Biomolecule Adducts......Page 165
Suggested Reading......Page 166
8.1 Introduction......Page 168
8.2.1 Whole Animal Studies......Page 169
8.3 Studies with Dispersed, Isolated Cells......Page 170
8.3.1 Tissue Digestion and Cell Separation......Page 171
8.3.3 Long-Term Suspension Culture......Page 173
8.4.1 Propagation of Primary and Passaged Cultures......Page 174
8.4.2 Immortalized Cells......Page 175
8.4.3 Modifications to Monolayer Cell Culture......Page 176
8.5 Observation of Cultured Cells......Page 178
8.6.2 Cell Culture......Page 179
8.7 Artifacts and Confounders......Page 181
8.8 Replacement of Animal Testing with Cell Culture Models......Page 182
8.9 Conclusions......Page 183
Suggested Reading......Page 184
9.1 Introduction......Page 186
9.2.1 CYP Gene Families and Subfamilies......Page 187
9.2.2 Pseudogenes and Alternate Splice Variants......Page 188
9.3 Cytochrome P450 Structure......Page 190
9.4.1 Catalytic Cycle......Page 193
9.4.3 Substrate Specificity and Overlap......Page 194
9.4.4 Endogenous Substrates......Page 196
9.5.1 Tissue Distribution......Page 199
9.5.2 Constitutive and Inducible P450 Enzymes......Page 200
9.5.3 Aromatic Hydrocarbon Receptor Induction of P450s......Page 201
9.5.4 Phenobarbital Induction of P450s......Page 202
9.5.5 Induction of P450s by Peroxisome Proliferators......Page 204
9.5.6 Hormonal Regulation of P450s......Page 205
9.5.7 Nutritional Regulation of P450s......Page 206
9.5.9 Regulation of P450s by Nitric Oxide......Page 207
9.7 Reactive Oxygen Species......Page 208
9.8 Posttranslation Modification of P450s......Page 209
Suggested Reading......Page 210
10.1 Introduction......Page 212
10.2.1b Aliphatic Hydroxylations......Page 214
10.2.1c Dealkylation: O-, N-, and S-Dealkylation......Page 215
10.2.1f S-Oxidation......Page 217
10.2.1h Desulfuration and Ester Cleavage......Page 218
10.2.1i Cyanide Release......Page 219
10.2.2 The Flavin-Containing Monooxygenase (FMO)......Page 220
10.3.1 Alcohol Dehydrogenases......Page 224
10.3.3a Monoamine Oxidases......Page 225
10.3.4 Molybdenum Hydroxylases......Page 226
10.4 Cooxidation by Prostaglandin Synthetase......Page 227
10.5 Reduction Reactions......Page 228
10.5.1 Nitro Reduction......Page 229
10.5.7 Reduction of Double Bonds......Page 230
10.6 Hydrolysis......Page 231
10.7.1 Microsomal Epoxide Hydrolase......Page 232
10.7.2 Cytosolic Epoxide Hydrolase......Page 233
10.8 DDT Dehydrochlorinase......Page 234
10.9.2 Inhibition......Page 235
10.9.3 Activation in Vitro......Page 239
10.9.4 Synergism and Potentiation......Page 240
Suggested Reading......Page 241
11.1 Introduction......Page 244
11.2 Polymorphisms in CYP Isoforms......Page 246
11.2.3 CYP2C19......Page 248
11.2.5 Other CYP Polymorphisms......Page 249
11.3 Polymorphisms in Alcohol Dehydrogenase......Page 250
11.6 Polymorphisms in Epoxide Hydrolase......Page 251
11.9 Polymorphisms: Mechanistic Classification......Page 252
11.11 Methods Used for the Study of Polymorphisms......Page 254
11.12 Epidemiology......Page 256
Suggested Reading......Page 257
12.2 Conjugation Reactions......Page 258
12.3.1 Glucuronides......Page 260
12.3.2 The UGT Superfamily......Page 262
12.4 Sulfation......Page 263
12.4.1 The SULT Superfamily......Page 264
12.5.1 N-Methylation......Page 265
12.5.2 O-Methylation......Page 266
12.6.1 Acetylation......Page 267
12.6.2 Amino Acid Conjugation......Page 268
12.7 Glutathione S-Transferases......Page 269
12.7.1 Allosteric Regulation......Page 271
12.7.3 GST Regulation......Page 272
12.8 Cysteine S-Conjugate β-Lyase......Page 273
12.10 Phase II Activation......Page 274
12.12 Conclusions......Page 275
Suggested Reading......Page 276
13.1 Introduction......Page 278
13.2.1 UDP-Glucuronosyl Transferases......Page 279
13.2.2 Glutathione Synthesis and Glutathione S-Transferases......Page 282
13.2.3 N-Acetyltransferases......Page 286
13.2.4 Sulfotransferases......Page 288
13.3 The Antioxidant Responsive Element and Phase II Gene Regulation......Page 290
Suggested Reading......Page 294
14.1 Introduction......Page 296
14.2 Xenobiotic Metabolism During Development......Page 297
14.2.1 Embryogenesis......Page 298
14.2.2 Xenobiotic Metabolism in the Neonate......Page 299
14.2.2b Weaning to Solid Foods......Page 300
14.2.4 Puberty and Adulthood......Page 301
14.2.6 Effects of Disease......Page 305
14.3 Effects of Pregnancy on Maternal Xenobiotic Metabolism......Page 307
14.5 Cycles in Development......Page 308
Suggested Reading......Page 310
15.1 Transport as a Determinant of Xenobiotic Action......Page 312
15.2 Factors Affecting Membrane/Tissue Permeability......Page 313
15.2.1 Cellular Level Transport......Page 314
15.2.2 Tissue Level Transport......Page 315
15.3.1 Transporter Families......Page 317
15.3.1a ABC Transporters......Page 319
15.3.1d Organic Anion Transporting Polypeptides (OATPs; SLC21A)......Page 320
15.3.2 Determining the Molecular Basis for Transport in Cells and Tissues......Page 321
15.4.1 Competition for Transport......Page 322
15.4.2b Transporter Function......Page 323
Suggested Reading......Page 324
16.1 Introduction......Page 326
16.2.3 Hyperplasia......Page 327
16.2.6 Dysplasia......Page 328
16.3 Cell Injury and Cell Death......Page 329
16.3.1d Microbial Agents......Page 330
16.3.2 Pathogenesis of Reversible Versus Irreversible Cell Injury......Page 331
16.3.3 Mechanisms of Irreversibility in Cell Injury......Page 332
16.4.1 Cell Swelling (Hydropic Degeneration)......Page 335
16.4.2a Coagulative Necrosis......Page 336
16.4.2d Liquefactive Necrosis......Page 337
16.5 Apoptosis......Page 338
16.5.1 Morphology of Apoptosis......Page 339
16.5.2 Mechanisms of Apoptosis......Page 340
16.5.2a Biochemical Features......Page 343
16.5.2b Extrinsic Pathway......Page 344
16.5.2c Perforin/Granzyme Pathway......Page 345
16.5.2d Intrinsic Pathway......Page 346
16.5.2e Execution Pathway......Page 347
16.5.3 Physiologic Apoptosis......Page 349
16.5.4 Pathologic Apoptosis......Page 350
16.5.5 Assays for Apoptosis......Page 352
16.5.5b DNA Fragmentation......Page 353
16.5.5c Detection of Caspases, Cleaved Substrates, Regulators, and Inhibitors......Page 354
16.5.5e Detection of Apoptosis in Whole Mounts......Page 355
Suggested Reading......Page 356
17.2.1 Structure: Outer and Inner Membranes......Page 358
17.2.2 Generating High-Energy Electrons (TCA Cycle, Fatty Acid Oxidation, FADH(2), and NADH)......Page 359
17.2.3 Respiratory Chain (Complex I, II, III, and IV, Ubiquinone, Cytochrome c, Proton Pump, Membrane Potential, Proton Active Force)......Page 360
17.2.4 Permeability Transition Pore (VDAC, ANT)......Page 361
17.3.2 Caspase Activation: Effector and Inhibitor Caspases......Page 362
17.3.3 Mitochondria Are “Poison Cabinets”......Page 363
17.3.4 Interplay of Bc12 Family (BH3-only, Bcl2, Bax/Bak)......Page 365
17.3.5 Permeability Transition Pore Opening......Page 367
17.3.6 Cross-Talk of Bax/Bak and PTP Opening Pathways......Page 368
17.4.1 Electron Transport Inhibitors......Page 369
17.4.3 Uncouplers......Page 370
Suggested Reading......Page 371
18.1 Introduction......Page 372
18.2 Glutathione-Dependent Conjugation of Chemicals......Page 373
18.3.2 GSH-Dependent Biologically Reactive Intermediates......Page 374
18.4.1 Introduction......Page 375
18.4.2 The Organization of Antioxidant Defense Against Oxidative Stress......Page 377
18.4.3 Superoxide Dismutase (SOD) Defense......Page 378
18.4.5 Organelle Glutathione Protection Against Oxidative Stress......Page 379
18.5.1 Glutathione-Dependent Protection......Page 382
18.5.2 Depletion of Glutathione by Chemicals and Fasting......Page 387
18.5.3 Glutathione Compartmentation and Chemical-Induced Injury......Page 388
18.5.4 Glutathione Redox Cycle......Page 389
18.5.5 Regulation of Glutathione Biosynthesis......Page 392
18.6.2 Role of Protein Sulfenic Acids......Page 393
18.6.3 Glutathionylation Induced by Nitric Oxide......Page 394
18.6.6 Protein Glutathionylation as a Regulatory Response......Page 395
Suggested Reading......Page 396
19.1.1 A Brief History of the Concept of Receptors......Page 398
19.1.3 Is There a Normal Function for Toxicant Receptors?......Page 399
19.1.4 Functional Biochemistry of Toxicant Receptors......Page 401
19.1.6a Definitions......Page 402
19.2.1 G-Protein-Coupled Receptors (GPCRs)......Page 403
19.2.2 Ionotropic Receptors (Ligand-Gated Ion Channels)......Page 405
19.2.4 Enzyme-Linked Receptors......Page 406
19.2.6 The Importance of Understanding Toxicant–Receptor Interactions......Page 407
19.3.1 Development of Radioligand Binding Assays......Page 408
19.3.2a Law of Mass Action and Fractional Occupancy......Page 409
19.3.2b The Theoretical Basis for Characterizing Receptors Using Saturation Radioligand Assays......Page 411
19.3.2c Experimental Forms of Data from Saturation Radioligand Assays......Page 414
19.3.3 Kinetic Determinations of Equilibrium Constants......Page 416
19.3.4 Competition Binding Assays......Page 417
19.3.4b The Hill Plot......Page 419
19.3.4c Visual Inspection of Binding Data......Page 420
19.3.4d Complex Binding Phenomena......Page 422
19.3.5b Methods to Estimate Nonspecifically Bound Ligand......Page 423
19.3.6 The Relation Between Receptor Occupancy and Biological Response......Page 424
19.4.2 Evolving Concepts of Receptor-Induced Functional Changes......Page 426
Suggested Reading......Page 427
20.1 Introduction......Page 428
20.2.1a Cytochrome P450......Page 429
20.2.1b Flavin-Containing Monooxygenase......Page 431
20.2.1c Prostaglandin Synthetase......Page 432
20.2.2 Phase II Conjugations......Page 433
20.2.3 Intestinal Microflora......Page 434
20.3 Stability of Reactive Metabolites......Page 435
20.4.3 Genetic and Physiological Factors......Page 437
20.4.5 DNA Adduct Formation......Page 438
20.5 Reactive Oxygen Species and Toxicity......Page 440
20.5.1 Generation and Detoxication of Reactive Oxygen Species......Page 441
20.5.2 Oxidative DNA Damage......Page 444
20.5.3 Protein Oxidation......Page 446
20.5.4 Lipid Peroxidation......Page 447
Suggested Reading......Page 449
21.1 Introduction......Page 452
21.1.1 Importance of Essential Metals in Physiological Systems......Page 454
21.1.2 Examples and Causes of Essential Metal Deficiency......Page 456
21.2 Understanding Metal Ion Reactions in Biological Systems......Page 458
21.2.1 Metal Complexation with Biological Molecules......Page 459
21.2.2 Nieboer and Richardson’s Metal Classification Scheme......Page 460
21.3 Modes of Metal Toxicity......Page 461
21.4 Metals and Oxidative Stress......Page 462
21.5.1 Introduction......Page 463
21.5.3 Function......Page 464
21.5.5 Isoforms......Page 465
21.5.6 Induction and Regulation of MT Gene Expression......Page 466
21.6.1 Cadmium......Page 467
21.6.2 Lead......Page 471
21.6.3 Mercury......Page 473
21.7 Metals and Cancer......Page 475
Suggested Reading......Page 477
22.1 Introduction......Page 480
22.2.2 Base Deamination......Page 481
22.2.4 Oxidative DNA Damage......Page 483
22.2.5 DNA Adducts Formed from Lipid Peroxidation Products......Page 487
22.2.6 DNA Methylation......Page 489
22.2.7a Incorporation of Uracil into DNA......Page 490
22.2.7c Incorporation of 8-Oxoguanine into DNA......Page 491
22.3.1 Mechanisms of Ionizing Radiation-Induced DNA Damage......Page 492
22.3.1a Base Damage and Double-Strand Breaks......Page 493
22.3.1b Multiple Damaged Sites and Double-Strand Breaks......Page 494
22.3.2a The Major UV Lesions: Cyclobutane Pyrimidine Dimers and (6–4) Photoproducts......Page 495
22.3.3 DNA Damage by Chemicals......Page 497
22.3.3a DNA Damaging Chemicals without Metabolic Activation......Page 498
22.3.3b DNA Damaging Chemicals that Require Metabolic Activation......Page 501
22.4.1 Definition of Terms......Page 505
22.4.1a General Terms......Page 506
22.4.1b Terms Based on Phenotypic Consequences......Page 507
22.4.2 Origin of Mutagenesis......Page 508
22.4.3 Biological Significance of Mutagenesis......Page 509
22.5.1 Chromosomal Aberrations......Page 510
22.5.3 DNA Damage Tolerance......Page 512
22.5.4 Error-Prone Translesion Synthesis Is the Major Mechanism of Base Damage-Induced Mutagenesis......Page 514
22.5.5 Base-Damage-Induced Mutagenesis is a Major Component of the SOS Response in E. coli......Page 516
22.5.6a The Rad6–Rad18 Complex Is a Ubiquitin Ligase Complex......Page 517
22.5.6b Rev3–Rev7 Complex Forms the Translesion Polymerase Polζ......Page 518
22.5.7a Rev1 Is a dCMP Transferase......Page 519
22.5.7c DNA Polymerase κ......Page 520
22.5.7e Common Biochemical Properties of the Y Family of DNA Polymerases......Page 521
22.5.8 Mechanistic Models of Translesion Synthesis......Page 522
22.5.9 Control of Translesion Synthesis and Mutagenesis......Page 523
22.5.10a AP Sites......Page 524
22.5.10b UV Photoproducts......Page 525
22.5.10c BPDE-N(2)-dG Adducts......Page 526
22.5.11 Translesion Synthesis and Immunology: Somatic Hypermutation......Page 527
Suggested Reading......Page 530
23.1 Introduction......Page 532
23.2.1 UV Radiation......Page 534
23.2.2 Alkylation Damage......Page 537
23.3 Base Excision Repair......Page 541
23.3.1 Glycosylases......Page 542
23.3.1a Uracil......Page 543
23.3.1c Oxidized and Fragmented Bases......Page 544
23.3.2 AP Endonucleases......Page 546
23.3.3 Repair Synthesis and Ligation......Page 547
23.4 Nucleotide Excision Repair......Page 548
23.4.1 DNA Damage Recognition......Page 549
23.4.2 NER in E. coli......Page 550
23.4.3 NER in Mammalian Cells......Page 552
23.4.4 NER and Transcription......Page 554
23.4.5 Human Diseases......Page 556
23.5.1 MMR in E. coli......Page 558
23.5.2 MMR in Mammalian Cells......Page 561
23.5.3 MMR and Cancer......Page 562
23.6.1 Double-Strand Break Repair in E. coli......Page 563
23.6.2 Double-Strand Break Repair in Eukaryotic Cells......Page 565
23.6.3 Interstrand Crosslink Repair......Page 567
23.7.2 Chromatin Remodeling in DNA Repair......Page 569
23.8 DNA Damage and Cell Cycle Checkpoints......Page 570
23.8.1 DNA Damage Sensing: ATM and ATR......Page 571
23.8.2 Mediators and Adaptors......Page 572
23.8.3 Effector Targets......Page 573
Suggested Reading......Page 574
24.1 Introduction and Historical Perspective......Page 576
24.2 Human Cancer......Page 577
24.2.1 Causes, Incidence, and Mortality Rates......Page 580
24.2.2 Classification of Carcinogens......Page 584
24.3.2 Epigenetic Agents......Page 589
24.4.1 Electrophilic Theory, Metabolic Activation, and DNA Adducts......Page 591
24.4.2 DNA Damage......Page 594
24.4.3 Complete Carcinogenesis Model......Page 595
24.6 Multistage Tumorigenesis......Page 596
24.6.1 Initiation–Promotion Model......Page 598
24.6.2 Mechanisms of Tumor Promotion......Page 599
24.7.1 Acute Transforming Retroviruses......Page 601
24.7.3 DNA Oncogenic Viruses......Page 603
24.8.1 Cell Transformation; Role of Carcinogens and Oncogenes......Page 604
24.8.2 Activation of Proto-oncogenes to Oncogenes......Page 605
24.8.3 Oncogenes and Signal Transduction......Page 607
24.8.4b Receptor Tyrosine Kinases as Oncogenes......Page 608
24.8.4d Guanosine Triphosphatases as Oncogenes......Page 610
24.8.4f Transcription Factors as Oncogenes......Page 613
24.8.5 Oncogene Cooperation......Page 614
24.9 Tumor Suppressor Genes......Page 615
24.9.1 Retinoblastoma Gene and the Cell Cycle......Page 616
24.9.3 pRB Is Altered in Tumorigenesis by Multiple Mechanisms......Page 618
24.9.4 p53......Page 619
24.9.5 p14(ARF)......Page 621
24.10 Mutator Phenotype/DNA Stability Genes......Page 622
24.11.1 Colonic Tumorigenesis in Humans......Page 623
24.13 Conclusions......Page 624
Suggested Reading......Page 625
25.1 Introduction and Historical Perspective......Page 626
25.2 Genetic Toxicology and Risk Assessment (General Considerations)......Page 628
25.3.1 DNA Damage and Repair Assays......Page 629
25.3.2 Gene Mutation Assay: Salmonella typhimurium......Page 630
25.3.4a Gene Mutation Assays......Page 631
25.3.4b Cytogenetic Assays......Page 632
25.3.5a Gene Mutation Assays......Page 635
25.3.6a Drosophila Sex-Linked Recessive Lethal Test (SLRL)......Page 636
25.3.7 Summary of Genotoxicity Assays......Page 637
25.3.8 Modifiers of Genetic Response......Page 638
25.3.9 Test Batteries for Detecting Carcinogens......Page 639
25.4 Use of Mechanistic Data in Cancer and Genetic Risk Assessments (Specific Considerations)......Page 641
25.5 New Research Directions......Page 643
25.6 Conclusions......Page 644
Suggested Reading......Page 645
26.1 Introduction......Page 646
26.2 Basic Concepts in Epidemiology......Page 647
26.2.1a Descriptive Studies......Page 648
26.2.1b Observational Analytical Studies......Page 649
26.2.2 Measuring Occurrence and Associations......Page 651
26.2.2b Measures of Association......Page 652
26.2.3 Evaluating Random Error: Confidence Intervals, Statistical Testing, and Statistical Power......Page 654
26.2.4a Selection Bias......Page 655
26.2.5 Evaluating Confounding......Page 656
26.2.6 Evaluating Interaction or Effect Modification......Page 658
26.3 Biomarkers Used in Molecular Epidemiology......Page 659
26.3.1 Identification and Validation of Biomarkers......Page 660
26.3.1b Applied Transitional Studies......Page 661
26.3.2 Biomarkers of Exposure......Page 662
26.3.2a Biomarkers of Internal Dose......Page 663
26.3.2b Biologically Effective Dose......Page 664
26.3.3 Biomarkers of Response or Outcome......Page 665
26.3.3a Stage of Events......Page 666
26.3.3d Preclinical Biomarkers......Page 667
26.4 Biomarkers of Genetic Susceptibility......Page 668
26.4.1 Types of Genetic Variants......Page 669
26.4.3 Gene–Environment Interactions......Page 671
26.4.4a Population Admixture......Page 673
26.5 Summary and Concluding Remarks......Page 674
Suggested Reading......Page 675
27.2 Anatomy and Function of the Respiratory Tract......Page 678
27.2.1 Upper Respiratory Tract as a Site of Toxicity......Page 681
27.2.3 Airways of the Lower Respiratory Tract......Page 683
27.2.4 Parenchyma of the Lower Respiratory Tract......Page 685
27.2.5 Circulatory, Lymphatic, and Nervous System of the Lung......Page 688
27.3 Toxicant-Induced Lung Injury, Remodeling, and Repair......Page 689
27.3.1 Oxidative Stress and Lung Injury......Page 691
27.3.2 Antioxidant Mechanisms in the Lung......Page 693
27.3.3 Oxidants and Cell Signaling in the Lung......Page 694
27.3.4 Respiratory Tract Injury from Inhaled Particles and Fibers......Page 696
27.3.5 Particle and Fiber Deposition and Clearance......Page 697
27.3.6 Respiratory Tract Injury from Gases and Vapors......Page 699
27.4.1 Pulmonary Fibrosis......Page 701
27.4.2 Asthma......Page 703
27.4.3 Hypersensitivity Pneumonitis......Page 706
27.4.4 COPD......Page 707
27.4.5 Lung Cancer......Page 708
Suggested Reading......Page 709
28.1 Introduction......Page 710
28.2 Liver Organization and Cellular Components......Page 711
28.2.1 Regional Differences of Lobular Function......Page 712
28.2.3 Nonparenchymal Liver Cells......Page 713
28.3 Types of Chemically Induced Lesions......Page 714
28.4.1 Fatty Liver......Page 716
28.4.2 Fibrosis......Page 717
28.4.3 Cholestasis......Page 718
28.4.4 Necrosis and Apoptosis......Page 719
28.4.5 Oxidative Stress......Page 720
28.5.1 Metabolism-Dependent......Page 724
28.6.1 Clinical......Page 725
28.6.2 Experimental......Page 726
28.7.1 Drugs......Page 727
28.7.4 Pesticides......Page 728
28.8 Conclusion......Page 729
Suggested Reading......Page 730
29.2.1 Structural Organization of the Kidney......Page 732
29.2.3 Renal Vasculature and Glomerular Filtration......Page 733
29.2.3b Morphologic Basis for Glomerular Filtration......Page 734
29.2.3f Juxtaglomerular Apparatus and Renin Secretion......Page 736
29.2.4 Tubular Function and Formation of Urine......Page 737
29.2.4b Loop of Henle and Countercurrent System......Page 738
29.2.4d Collecting Duct......Page 739
29.3 Factors Contributing to Nephrotoxicity......Page 740
29.4.1 In Vivo Methods......Page 741
29.4.2 In Vitro Methods......Page 743
29.4.3 Histopathology......Page 744
29.5.1 Glomerulus as a Site of Toxicity......Page 745
29.5.3 Aminoglycoside Nephrotoxicity: Role of Proximal Tulular Reabsorption......Page 748
29.5.3a Renal Handling of Aminoglycosides......Page 749
29.5.3b Biochemical Mechanisms in Aminoglycoside Cytotoxicity......Page 750
29.5.4a Renal Handling of Cephalosporins......Page 752
29.5.4b Biochemical Mechanism of Cephalosporin Cytotoxicity......Page 753
29.5.5 Chloroform Nephrotoxicity: Role of Metabolic Bioactivation......Page 755
29.5.6 Mercury Nephrotoxicity: Role of Molecular Mimicry......Page 757
29.5.7 Loop of Henle as a Site of Toxicity......Page 758
29.5.8 Distal Tubule as a Site of Injury......Page 759
29.5.9 Collecting Tubules as a Site of Injury......Page 760
29.5.10 Crystalluria......Page 761
29.6 Summary......Page 762
Suggested Reading......Page 763
30.1 Introduction......Page 764
30.2 Specialized Aspects of Neuronal Metabolism......Page 768
30.2.1 Anterograde Axonal Transport......Page 769
30.3 Specialized Aspects of Schwann Cell Transport......Page 770
30.4.1 Selective Vulnerability......Page 771
30.4.2 Characteristics of Axonal Neuropathies......Page 772
30.4.3a Inhibitors of Energy Production......Page 774
30.4.3c Structural Components of the Axon as Sites of Vulnerability......Page 775
30.4.4 Characteristics of Demyelinating Neuropathies......Page 776
30.4.5 Biochemical Mechanisms of Demyelination......Page 777
30.5 Conclusion......Page 778
Suggested Reading......Page 779
31.1 Introduction......Page 782
31.2.1 Neuronal Targets......Page 783
31.2.2 Glial Targets......Page 785
31.2.3 Vascular and Extracellular Targets......Page 788
31.3.1a Genetic Determinants of Susceptibility......Page 789
31.3.1b Epigenetic Determinants......Page 790
31.3.2 Susceptibility in Development and Aging......Page 791
31.3.3 Interacting Endogenous and Environmental Factors......Page 793
31.4.1a Disruption of Critical Structure and Function......Page 794
31.4.1b Molecular and Biochemical CNS Responses to Cytotoxic Stress......Page 796
31.4.2a Antioxidants, Innate Immunity, and Neurotrophism......Page 797
31.4.2b The Blood–Brain Barrier......Page 800
31.5 The Dynamic Nervous System: Adaptibility, Plasticity, and Repair......Page 802
Suggested Reading......Page 803
32.1 Introduction......Page 804
32.2.2 Innate Responses......Page 806
32.2.3 Acquired Immune Responses......Page 808
32.3.1 Identifying Immune Suppressants......Page 812
32.3.2 Identifying Proteins and Chemicals that Cause or Exacerbate Allergic Disease......Page 814
32.4.1 Cyclosporin A and Glucocorticoids......Page 816
32.4.2 Halogenated Aromatic Hydrocarbons......Page 818
32.4.3 Ultraviolet Radiation......Page 821
32.4.4 Cyclophosphamide......Page 823
32.4.5 Polycyclic Aromatic Hydrocarbons......Page 824
32.4.6 Organic Solvents......Page 826
32.4.7 Summary of Immunosuppressive Mechanisms......Page 827
32.5.1 Classification of Immune-Mediated Injury Based on Mechanisms......Page 828
32.5.2 Features Common to Respiratory and Dermal Allergies......Page 829
32.5.3 Respiratory Allergy/Allergic Asthma......Page 830
32.5.5 Allergic Contact Dermatitis (Contact Hypersensitivity)......Page 832
32.5.6 Delayed-Type Hypersensitivity in the Lung......Page 834
32.5.8 Adjuvants......Page 835
32.6.2 Mechanisms of Autoimmunity......Page 837
32.6.4 The Role of Environmental Factors in Autoimmune Disease......Page 839
Suggested Reading......Page 841
33.2 General Principles of Reproductive Toxicology......Page 844
33.2.2 Cell Signaling and Endocrine Disruption......Page 845
33.3 Sexual Differentiation......Page 846
33.4 Neuroendocrine Regulation of Reproduction......Page 848
33.4.1 Neuroendocrine Control of the Ovarian Cycle in Females......Page 850
33.4.2a GnRH Analogs......Page 851
33.5 Male Reproductive System......Page 852
33.5.1 Testes......Page 853
33.5.1a Spermatogenesis......Page 854
33.5.1b Sertoli Cells......Page 855
33.5.2c Leydig Cells and Steroidogenesis......Page 857
33.5.2 Efferent Ducts and Epididymes as Targets for Toxicants......Page 858
33.5.3 Male Accessory Sex Glands......Page 859
33.6.1a Embryonic Development of Female Germ Cells......Page 860
33.6.1b Folliculogenesis and Steroidogenesis......Page 861
33.6.1c Ovulation and Luteinization......Page 864
33.6.3 Uterine Cycle, Implantation, and Pregnancy......Page 865
33.6.5 Lactation......Page 866
33.7 General Categories of Reproductive Toxicants......Page 868
Suggested Reading......Page 869
34.1 Introduction......Page 870
34.2.1 Embryonic Period......Page 871
34.2.1a Sonic Hedgehog Signaling in Limb Morphogenesis......Page 872
34.2.1b Homeobox (HOX) Genes and Body Segmentation......Page 874
34.2.2 Fetal Period......Page 875
34.3.1 Role of Gene–Gene and Gene–Environment Interactions......Page 876
34.3.2 Susceptibility Varies with Gestational Age......Page 877
34.3.4 Final Manifestations of Developmental Toxicity......Page 878
34.3.5 Nature of the Toxicant Determines Access to the Conceptus......Page 879
34.4 Selected Examples of Developmental Toxicants......Page 880
34.4.1 Anticonvulsants......Page 881
34.4.2 Cyclophosphamide......Page 882
34.4.3 Diethylstilbestrol......Page 884
34.4.4 Retinoids......Page 885
34.4.5 Thalidomide......Page 886
Suggested Reading......Page 887
35.2 Functions of Skin......Page 890
35.3 Epidermis......Page 891
35.3.1a Stratum Corneum......Page 892
35.3.1e Stratum Basale......Page 893
35.3.2c Langerhans Cells......Page 894
35.3.4 Basement Membrane......Page 895
35.3.6 Appendageal Structures......Page 896
35.3.9 Eccrine Sweat Glands......Page 898
35.4.1 Species Differences......Page 899
35.4.3 Hair Follicles......Page 900
35.4.5 Age......Page 901
35.4.8 Summary......Page 902
35.5 Percutaneous Absorption and Penetration......Page 903
35.5.1 Dermatopharmacokinetics......Page 904
35.5.2 Routes of Absorption and Penetration......Page 905
35.5.3 Factors and Chemicals that Affect Percutaneous Absorption......Page 906
35.5.4 Experimental Techniques Used to Assess Absorption......Page 907
35.6 Dermatotoxicity......Page 908
35.6.1 Mechanisms of Keratinocyte Mediation of Skin Irritation/Inflammation......Page 909
35.6.2 Cell Death: Apotosis or Necrosis......Page 911
35.6.3 Irritancy Testing Protocols......Page 913
35.6.4 Phototoxicity......Page 914
35.6.5 Vesication......Page 916
35.7 Dermal Toxicity of Nanoparticles......Page 917
Suggested Reading......Page 918
Index......Page 920