(PDF) Translational Toxicology and Therapeutics by Michael D. Waters

This is the PDF eBook version for Translational Toxicology and Therapeutics – Windows of Developmental Susceptibility in Reproduction and Cancer by Michael D. Waters, Claude L. Hughes

Table of Contents

List of Contributors xix

Part One Introduction: The Case for Concern about Mutation and Cancer Susceptibility during Critical Windows of Development and the Opportunity to Translate Toxicology into a Therapeutic Discipline 1

1 What Stressors Cause Cancer and When? 3
Claude L. Hughes and Michael D. Waters

1.1 Introduction 3

1.1.1 General Information about Cancer 5

1.1.2 Stressors and Adaptive Responses 8

1.2 What Stressors Cause Cancer and When? 8

1.2.1 Mutagenic MOAs 13

1.2.1.1 DNA Repair 14

1.2.2 Epigenetic MOAs 16

1.2.3 Nongenotoxic Carcinogens, ROS, Obesity, Metabolic, Diet, Environment, Immune, Endocrine MOAs 20

1.2.4 Tumor Microenvironment MOAs 25

1.3 Relevance of Circulating Cancer Markers 26

1.4 Potential Cancer Translational Toxicology Therapies 29

1.4.1 Well-Established/Repurposed Pharmaceuticals 31

1.4.2 GRAS/GRASE, Diet, and Nutraceuticals 34

1.4.2.1 Suppression of Cell Proliferation and Induction of Cell Death 35

1.4.2.2 Anti-Inflammatory Effects: Insights from Various Diseases 36

1.4.2.3 Upregulation of Tumor Suppressor MicroRNAs 38

1.4.2.4 Regulation of Oxidative Stress 38

1.4.2.5 Activation of Signal Transduction Pathways 39

1.4.2.6 Mitigating Inherited Deleterious Mutations 40

1.4.2.7 Mitigating Adverse Epigenetic States 42

1.4.2.8 Paradigm for Study of Cancer Chemoprevention 43

1.5 Modeling and the Future 47

References 51

2 What Mutagenic Events Contribute to Human Cancer and Genetic Disease? 61
Michael D. Waters

2.1 Introduction 61

2.1.1 Childhood Cancer, Developmental Defects, and Adverse Reproductive Outcomes 62

2.1.2 Newborn Screening for Genetic Disease 62

2.1.3 Diagnosis of Genetic Disease 63

2.1.4 Familial and Sporadic Cancer 65

2.2 Genetic Damage from Environmental Agents 67

2.3 Testing for Mutagenicity and Carcinogenicity 71

2.4 Predictive Toxicogenomics for Carcinogenicity 73

2.5 Germ Line Mutagenicity and Screening Tests 76

2.6 Reproductive Toxicology Assays in the Assessment of Heritable Effects 80

2.6.1 Segmented Reproductive Toxicity Study Designs 80

2.6.2 Continuous Cycle Designs 81

2.6.2.1 One-Generation Toxicity Study 81

2.6.2.2 Repeat Dose Toxicity Studies 82

2.7 Assays in Need of Further Development or Validation 82

2.7.1 Transgenic Rodent Gene Mutation Reporter Assay 82

2.7.2 Expanded Simple Tandem Repeat Assay 84

2.7.3 Spermatid Micronucleus (MN) Assay 85

2.7.4 Sperm Comet Assay 86

2.7.5 Standardization of Sperm Chromatin Quality Assays 86

2.8 New Technologies 87

2.8.1 Copy Number Variants and Human Genetic Disease 87

2.8.2 Next-Generation Whole Genome Sequencing 88

2.8.3 High-Throughput Analysis of Egg Aneuploidy in C. elegans, and Other Alternative Assay Systems 90

2.9 Endpoints Most Relevant to Human Genetic Risk 91

2.10 Worldwide Regulatory Requirements for Germ Cell Testing 94

2.11 Conclusion 95

Acknowledgments 96

References 96

3 Developmental Origins of Cancer 111
Suryanarayana V. Vulimiri and John M. Rogers

3.1 Introduction 111

3.2 Current Trends in Childhood Cancer 112

3.3 Potential Mechanisms of Prenatal Cancer Induction 113

3.4 Ontogeny of Xenobiotic Metabolizing Enzymes and DNA Repair Systems 113

3.5 The Developmental Origins of Health and Disease (DOHaD) Theory 115

3.6 Epigenetic Regulation during Development 115

3.6.1 Critical Periods for Epigenetic Regulation 116

3.7 Mechanisms of Cancer in Offspring from Paternal Exposures 117

3.8 Parental Exposures Associated with Cancer in Offspring 118

3.8.1 Radiation 118

3.8.2 Diethylstilbestrol 119

3.8.3 Tobacco Smoke 120

3.8.4 Pesticides 122

3.8.5 Arsenic 123

3.9 Models for the Developmental Origins of Selected Cancers 124

3.9.1 Breast Cancer 124

3.9.2 Leukemia 127

3.10 Public Health Agencies’ Views on Prenatal Exposures and Cancer Risk 129

3.10.1 The United States Environmental Protection Agency (US EPA) 129

3.10.2 The California Environmental Protection Agency (CalEPA) 131

3.10.3 Washington State Department of Ecology (WA DoE) 133

3.11 Conclusions 134

Acknowledgment 135

References 135

4 The Mechanistic Basis of Cancer Prevention 147
Bernard W. Stewart

4.1 Introduction 147

4.2 A Mechanistic Approach 147

4.2.1 Specifying Carcinogens 148

4.2.2 Cancer Risk Factors Without Carcinogen Specification 148

4.3 Preventing Cancer Attributable to Known Carcinogens 149

4.3.1 Involuntary Exposure 149

4.3.1.1 Infectious Agents 149

4.3.1.2 Occupation 150

4.3.1.3 Drugs 151

4.3.1.4 Pollution 152

4.3.1.5 Dietary Carcinogens 152

4.3.2 Tobacco Smoking 153

4.3.2.1 Measures to Limit Availability and Promotion 154

4.3.2.2 Product Labeling, Health Warnings, and Usage Restrictions 154

4.3.2.3 Smoking Cessation 155

4.3.3 Alcohol Drinking 155

4.3.4 Solar and Ultraviolet Radiation 156

4.4 Prevention Involving Complex Risk Factors 157

4.4.1 Workplace Exposures 157

4.4.2 Diet and Overweight/Obesity 157

4.5 Prevention Independent of Causative Agents or Risk Factors 158

4.5.1 Screening 158

4.5.2 Chemoprevention 159

4.6 Conclusion 160

References 160

Part Two Exposures that Could Alter the Risk of Cancer Occurrence, and Impact Its Indolent or Aggressive Behavior and Progression Over Time 171

5 Diet Factors in Cancer Risk 173
Lynnette R. Ferguson

5.1 Introduction 173

5.2 Obesity 174

5.3 Macronutrients 175

5.3.1 Protein 176

5.3.2 Lipids 177

5.3.3 Carbohydrates 178

5.4 Micronutrients 181

5.4.1 Vitamins 181

5.4.2 Minerals 184

5.5 Phytochemicals 184

5.5.1 Phytoestrogens 185

5.5.2 Other Phytochemicals 186

5.6 Conclusions 188

References 188

6 Voluntary Exposures: Natural Herbals, Supplements, and Substances of Abuse – What Evidence Distinguishes Therapeutic from Adverse Responses? 199
Eli P. Crapper, Kylie Wasser, Katelyn J. Foster, and Warren G. Foster

6.1 Introduction 199

6.1.1 Alcohol 200

6.1.2 Cigarette Smoking 201

6.1.3 Herbals and Supplements 202

6.1.3.1 Melatonin 202

6.1.3.2 Resveratrol 204

6.1.3.3 Dong Quai 205

6.1.3.4 Eleutherococcus 206

6.1.3.5 Saw Palmetto 206

6.1.3.6 Stinging Nettle 207

6.2 Summary and Conclusions 207

References 207

7 Voluntary Exposures: Pharmaceutical Chemicals in Prescription and Over-the-Counter Drugs – Passing the Testing Gauntlet 213
Ronald D. Snyder

7.1 Introduction 213

7.2 Testing of New Drug Entities for Genotoxicity 214

7.3 Relationship between Genotoxicity Testing and Rodent Carcinogenicity 217

7.4 Can Drug-Induced Human Cancer Be Predicted? 218

7.5 What Can Rodent Carcinogenicity Tell Us about Human Cancer Risk? 220

7.6 Genotoxicity Prediction Using “Traditional” In Silico Approaches 222

7.7 Covalent versus Noncovalent DNA Interaction 223

7.8 Use of New Technologies to Predict Toxicity and Cancer Risk: High-Throughput Methods 224

7.9 Transcriptomics 225

7.10 Single-Nucleotide Polymorphisms (SNPs) 226

7.11 Conclusions 227

Appendix A 228

References 253

8 Children’s and Adult Involuntary and Occupational Exposures and Cancer 259
Annamaria Colacci and Monica Vaccari

8.1 Introduction 259

8.2 Occupational Exposures and Cancer 262

8.2.1 Occupational Cancer in the Twenty-First Century 262

8.2.2 Past and Present Occupational Exposure to Asbestos 263

8.2.3 Toxicology of Fibers: What We Have Learned from the Asbestos Lesson 265

8.2.3.1 Mechanism and Mode of Action of Asbestos and Asbestos-Like Fibers in Carcinogenesis: The Role of Inflammation and Immune System to Sustain the Cancer Process 268

8.2.4 Occupational Exposures and Rare Tumors 270

8.3 Environmental Exposures and Cancer 271

8.3.1 Environmental Exposures and Disease: Is This the Pandemic of the Twenty-First Century? 271

8.3.2 The Complexity of Environmental Exposures 272

8.3.3 Environmental Impact on Early Stages of Life: Are Our Children at Risk? 274

8.3.4 Environmental Endocrine Disruptors: The Steps Set Out to Recover Our Stolen Future 277

8.3.5 From Occupational to Environmental Exposures: Asbestos and Other Chemicals of Concern 279

8.3.5.1 Asbestos 279

8.3.5.2 Arsenic and Arsenic Compounds 280

8.3.5.3 Phthalates 282

8.3.5.4 Pesticides 283

8.3.5.5 Mycotoxins 286

8.3.6 Air Pollution and Airborne Particulate Matter: The Paradigmatic Example of Environmental Mixtures 288

8.3.6.1 Characteristics of PM and PM Exposures 289

8.3.6.2 PM Exposures and Cancer 291

8.3.6.3 Possible Mechanisms of PM Toxicity 293

8.3.6.4 The Role of PM Exposures in the Fetal Origin of the Disease 294

8.4 Conclusions and Future Perspectives 296

References 299

Part Three Gene–Environment Interactions 317

9 Ethnicity, Geographic Location, and Cancer 319
Fengyu Zhang

9.1 Introduction 319

9.2 Classification of Cancer 320

9.2.1 Classification by Histology 320

9.2.2 Classification by Primary Location 322

9.3 Ethnicity and Cancer 323

9.3.1 Cancer Death and Incidence 323

9.3.2 Site-Specific Cancer Incidence 326

9.3.3 Site-Specific Cancer Incidence between the United States and China 328

9.4 Geographic Location and Cancer 331

9.4.1 Mapping Human Diseases to Geographic Location 331

9.4.2 Geographic Variation and Cancer in the United States 332

9.5 Ethnicity, Geographic Location, and Lung Cancer 334

9.5.1 Ethnic Differences 334

9.5.2 Geographic Variation 335

9.5.3 Individual Risk Factors 335

9.6 Common Cancers in China 338

9.6.1 Liver Cancer 339

9.6.1.1 Geographic Variation 339

9.6.1.2 Urban Residence and Sex 340

9.6.1.3 Hepatitis B Virus Infection 340

9.6.1.4 Familial Aggregation and Genetic Variants 341

9.6.2 Gastric Cancer 342

9.6.2.1 H. pylori 342

9.6.2.2 Familial Aggregation 343

9.6.2.3 Genetic Susceptibility Factors 343

9.6.3 Esophageal Cancer 344

9.6.3.1 Geographic Variation 344

9.6.3.2 Viral Infections 344

9.6.3.3 Familial Aggregation 345

9.6.3.4 Genetic Susceptibility Factors 345

9.6.4 Lung Cancer 346

9.6.5 Genetic Susceptibility Factors 347

9.6.6 Cervical Cancer 348

9.7 Cancer Risk Factors and Prevention 348

9.7.1 Environmental Chemical Exposure 348

9.7.2 Infectious Agents 349

9.7.3 Psychosocial Stress and Social Network 349

9.7.4 The Developmental Origin of Adult-Onset Cancer 350

9.7.5 Cancer Prevention and Intervention 351

References 353

10 Dietary/Supplemental Interventions and Personal Dietary Preferences for Cancer: Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 363
Sandeep Kaur, Elaine Trujillo, and Harold Seifried

10.1 Introduction 363

10.2 Gene Expression and Epigenetics 364

10.3 Environmental Lifestyle Factors Affecting Cancer Prevention and Risk 366

10.3.1 Obesity 366

10.3.2 Weight Loss 368

10.3.3 Physical Activity 369

10.4 Dietary Patterns 370

10.5 Complementary and Integrative Oncology Interventions/Restorative Therapeutics 373

10.6 Special and Alternative Diets 377

10.7 Popular Anticancer Diets 378

10.7.1 Macrobiotic Diet 378

10.7.2 The Ketogenic Diet 382

10.7.3 Fasting Diet 383

10.8 Conclusion 384

Acknowledgment 384

References 385

11 Social Determinants of Health and the Environmental Exposures: A Promising Partnership 395
Lauren Fordyce, David Berrigan, and Shobha Srinivasan

11.1 Introduction 395

11.1.1 Conceptual Model 397

11.1.2 Difference versus Disparity 398

11.2 Social Determinants of Health 399

11.2.1 Race/Ethnicity 399

11.2.2 Social Determinants of Health: “Place” and Its Correlates 402

11.2.3 Gender and Sexuality 405

11.3 Conclusions: Social Determinants of Health and Windows of

Susceptibility 407

Acknowledgments 408

References 408

Part Four Categorical and Pleiotropic Nonmutagenic Modes of Action of Toxicants: Causality 415

12 Bisphenol A and Nongenotoxic Drivers of Cancer 417
Natalie R. Gassman and Samuel H. Wilson

12.1 Introduction 417

12.2 Dosing 420

12.3 Receptor-mediated Signaling 421

12.4 Epigenetic Reprogramming 422

12.5 Oxidative stress 424

12.6 Inflammation and Immune Response 425

12.7 BPA-Induced Carcinogenesis 426

12.8 Fresh Opportunities in BPA Research 428

References 429

13 Toxicoepigenetics and Effects on Life Course Disease Susceptibility 439
Luke Montrose, Jaclyn M. Goodrich, and Dana C. Dolinoy

13.1 Introduction to the Field of Toxicoepigenetics 439

13.1.1 The Epigenome 440

13.1.2 Epigenetic Marks are Heritable and Reversible 440

13.1.3 DNA Methylation 441

13.1.4 Histone Modifications and Chromatin Packaging 442

13.1.5 Noncoding RNAs 443

13.1.6 Key Windows for Exposure-Related Epigenetic Changes 443

13.1.7 Evaluation of Environmentally Induced Epigenetic Changes in Animal Models and Humans 444

13.2 Exposures that Influence the Epigenome 444

13.2.1 Air Pollution 445

13.2.2 Metals 447

13.2.3 Endocrine Disrupting Chemicals (EDCs) 448

13.2.4 Diet 451

13.2.5 Stress 453

13.3 Intergenerational Exposures and Epigenetic Effects 454

13.4 Special Considerations and Future Directions for the Field of Toxicoepigenetics 456

13.4.1 Tissue Specificity 456

13.4.2 The Dynamic Nature of DNA Methylation 458

13.5 Future Directions 459

13.6 Conclusions 460

Acknowledgments 461

References 461

14 Tumor-Promoting/Associated Inflammation and the Microenvironment: A State of the Science and New Horizons 473
William H. Bisson, Amedeo Amedei, Lorenzo Memeo, Stefano Forte, and Dean W. Felsher

14.1 Introduction 473

14.2 The Immune System 475

14.2.1 Innate Immune Response 475

14.2.2 Adaptive Immune Response 478

14.3 Prioritized Chemicals 482

14.3.1 Bisphenol A 482

14.3.2 Polybrominated Diphenyl Ethers 483

14.3.3 4-Nonylphenol 485

14.3.4 Atrazine 485

14.3.5 Phthalates 486

14.4 Experimental Models of Carcinogenesis through Inflammation and Immune System Deregulation 487

14.5 Antioxidants and Translational Opportunities 493

14.6 Tumor Control of the Microenvironment 495

Acknowledgments 497

References 497

15 Metabolic Dysregulation in Environmental Carcinogenesis and Toxicology 511
R. Brooks Robey

15.1 Introduction 511

15.2 Metabolic Reprogramming and Dysregulation in Cancer 513

15.2.1 Carbohydrate Metabolism in Cancer 515

15.2.2 Lipid Metabolism in Cancer 519

15.2.3 Protein Metabolism in Cancer 521

15.3 Moonlighting Functions 523

15.4 Cancer Metabolism in Context 523

15.4.1 The Gestalt of Intermediary Metabolism 523

15.4.2 Cancer Tissues, Cells, and Organelles as Open Systems 527

15.4.3 The Endosymbiotic Nature of Cancer 527

15.4.4 Catabolic and Anabolic Support of Cell Proliferation 528

15.4.5 Cancer Heterogeneity 529

15.4.6 Phenotypic Relationships between Cancer Cells and Their Parental Cell Origins 532

15.4.7 Evolutionary Perspectives of Metabolic Fitness and Selection in Cancer Development 533

15.5 Dual Roles for Metabolism in Both the Generation and Mitigation of Cellular Stress 536

15.5.1 Metabolism and Oxidative Stress 537

15.5.2 Metabolism and Hypoxic Stress 539

15.5.3 Nutritional Stress and Metabolism 539

15.5.4 Metabolism and Physical Stress 540

15.5.5 Metabolism and Other Forms of Cellular Stress 541

15.6 Models of Carcinogenesis 541

15.6.1 Traditional Multistage Models of Cancer Development 542

15.6.2 Role of Replicative Mutagenesis in Cancer Development 543

15.6.3 Acquired Mismatch Model of Carcinogenesis 543

15.7 Potential Metabolic Targets for Environmental Exposures 546

15.7.1 Conceptual Overview of Potential Metabolic Targets 546

15.7.2 Identification of Key Targetable Contributors to Metabolic Dysregulation and Selection 549

15.7.2.1 Glycolysis 555

15.7.2.2 Lipogenesis, Lipolysis, and the PPP 555

15.7.2.3 Citric Acid Cycle 556

15.7.2.4 Organizational or Compartmental Targets 556

15.7.2.5 Metabolite Transport Mechanisms 557

15.7.2.6 Signal Transduction Effectors 558

15.8 Metabolic Changes Associated with Exposures to Selected Agents 559

15.8.1 Selected Agents Classified by the World Health Organization’s International Agency for Research on Cancer (IARC) 559

15.8.1.1 IARC Group 1 (Carcinogenic to Humans) 560

15.8.1.2 IARC Group 2A (Probably Carcinogenic to Humans) 564

15.8.1.3 IARC Group 2B (Possibly Carcinogenic to Humans) 565

15.8.1.4 Other Agents 565

15.8.2 Environmentally Relevant Combinatorial Exposures 567

15.8.2.1 Occupational and Common Environmental Exposures 567

15.8.2.2 Environmentally Relevant Low-Dose Combinatorial Exposures 568

15.8.2.3 The Halifax Project 570

15.9 A Conceptual Overview of Traditional and Emerging Toxicological Approaches to the Problem of Cancer Metabolism: Implications for Future Research 571

15.9.1 General Experimental Considerations in the Study of Metabolism In Vitro 571

15.9.2 Systems Biology and Current Approaches to In Vitro Toxicology Screening 573

15.10 The Nosology of Cancer and Cancer Development 577

15.11 Discussion 579

Acknowledgments 583

References 583

Part Five Biomarkers for Detecting Premalignant Effects and Responses to Protective Therapies during Critical Windows of Development 607

16 Circulating Molecular and Cellular Biomarkers in Cancer 609
Ilaria Chiodi, A. Ivana Scovassi, and Chiara Mondello

16.1 Introduction 609

16.2 Proteins in Body Fluids: Potential Biomarkers 610

16.2.1 Diagnostic Protein Biomarkers 612

16.2.2 Prognostic Protein Biomarkers 613

16.2.3 Protein Biomarkers of Drug Response 615

16.3 Circulating Cell-Free Nucleic Acids 615

16.3.1 Circulating Cell-Free Tumor DNA 616

16.3.1.1 Cf-DNA Integrity, Microsatellite Instability, and LOH 617

16.3.1.2 Tumor-Specific Genetic Alterations 617

16.3.1.3 Tumor Genetic Alterations and Therapy Resistance 619

16.3.1.4 Tumor Epigenetic Alterations: DNA Methylation 620

16.3.2 Circulating Cell-Free RNA 621

16.3.2.1 Circulating Cell-Free microRNA 621

16.4 Extracellular Vesicles: General Features 624

16.4.1 Classification of EVs 624

16.4.2 EVs and Cancer 625

16.4.3 EVs as Mediators of Cell-To-Cell Communication 627

16.5 Circulating Tumor Cells 628

16.5.1 Two-Step Processing of Blood Samples: Enrichment and Identification of Circulating Tumor Cells 628

16.5.1.1 CTC Number as a Cancer Biomarker 630

16.5.2 Characterization of CTCs 630

16.5.2.1 Molecular Characterization of CTCs 630

16.5.2.2 Functional Characterization of CTCs 632

16.5.3 Single CTCs versus CTC Clusters 634

16.5.4 In Hiding Before Getting Home, the Long Journey of CTCs 635

16.6 Conclusions 635

References 637

17 Global Profiling Platforms and Data Integration to Inform Systems Biology and Translational Toxicology 657
Barbara A. Wetmore

17.1 Introduction 657

17.2 Global Omics Profiling Platforms 659

17.2.1 Genomics 659

17.2.2 Epigenomics 661

17.2.3 Transcriptomics 662

17.2.4 Proteomics 665

17.2.5 Metabolomics 668

17.3 High-Throughput Bioactivity Profiling 669

17.3.1 High-Throughput Bioactivity and Toxicity Screening 669

17.3.2 In Vitro–In Vivo Extrapolation 671

17.4 Biomarkers 672

17.5 Exposomics 673

17.6 Bioinformatics to Support and Data Integration and Multiomics Efforts 674

17.7 Data Integration: Multiomics and High-Dimensional Biology Efforts 676

17.8 Conclusion 679

References 679

18 Developing a Translational Toxicology Therapeutic Portfolio for Cancer Risk Reduction 691
Rebecca Johnson and David Kerr

18.1 Introduction 691

18.2 The Identification of Novel Predictors of Adverse Events 693

18.2.1 Candidate Gene Studies 693

18.2.2 Genome-wide Associations 694

18.2.3 Next-Generation Sequencing 695

18.3 Proof of Principle Toxgnostics 696

18.4 Proposed Protocol 698

18.4.1 Integration within Randomized Control Trials 698

18.4.2 Biobanking and Future-Proofing Samples 699

18.4.3 Data Protection and Full Consent 702

18.4.4 The Need for a Collaborative Approach 703

18.4.5 Open Access to Results 704

18.4.6 Translation from Bench to Bedside 705

18.5 Fiscal Matters 706

18.6 The Future of Toxgnostics 706

References 707

19 Ethical Considerations in Developing Strategies for Protecting Fetuses, Neonates, Children, and Adolescents from Exposures to Hazardous Environmental Agents 711
David B. Resnik and Melissa J. Mills

19.1 Introduction 711

19.2 What Is Ethics? 712

19.2.1 Some Fundamental Ethical Values 712

19.2.1.1 Benefits and Costs 712

19.2.1.2 Individual Rights and Responsibilities 713

19.2.1.3 Justice 713

19.2.2 Value Conflicts and Ethical Decision-Making 713

19.3 Ethical Considerations for Strategies Used to Protect Fetuses, Neonates, Children, and Adolescents from Exposures to Harmful Environmental Agents 715

19.3.1 Education 715

19.3.2 Testing/Screening/Monitoring 717

19.3.3 Worker Protection 720

19.3.4 Government Regulation 722

19.3.5 Taxation 725

19.3.6 Civil Liability 726

19.3.7 Criminal Liability 729

19.4 Research with Human Participants 730

19.4.1 Return of Individualized Research Results 732

19.4.2 Protecting Privacy and Confidentiality 733

19.4.3 Interventional Studies 734

19.4.4 Intentional Exposure Studies 736

19.4.5 Protecting Vulnerable Participants 739

19.5 Conclusion 742

References 742

Index 751