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Dieses Fachbuch verbindet die Disziplinen Toxikologie und Therapeutika. Dabei werden die Belastung durch toxische Stoffe und genetische Mechanismen in Bezug zu Gesundheit und Entwicklung des Menschen gesetzt. Die Kapitel erläutern spezifische Zell- und molekulare Targets bekannter toxischer Stoffe, zeigen einen systematischen Ansatz zur Erkennung mutagener und reproduktionstoxischer Stoffe und erläutern therapeutische Ansätze, um Krebsrisiken zu senken. Die Publikation unterstützt die Entwicklung von Tiermodellen und Tests zur Bewertung toxischer Wirkungen auf die menschliche Gesundheit, vor allem Mutationen und Krebserkrankungen.
List 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 Epigeneti
About the author
MICHAEL D. WATERS, PhD, is an independent consultant with over 40 years of toxicology and toxicogenomics research experience at the EPA, at NIH/NIEHS and in the private sector. He has held adjunct professorships in toxicology and pharmacology at both the University of North Carolina and Duke University.
CLAUDE L. HUGHES, MD, PhD, is an Executive Director in the Therapeutic Science and Strategy Unit at QuintilesIMS. He is also an Adjunct Professor at North Carolina State University, and Wake Forest University as well as a Consulting Professor at Duke University Medical Center.
Summary
Written by leading research scientists, this book integrates current knowledge of toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity.
