Translational Toxicology and Therapeutics

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.

Auteur

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.

Texte du rabat

Translational toxicology aims to identify applicable therapeutics that can safely and effectively mitigate potential harm from natural as well as anthropogenic environmental exposures. Written by leading research scientists, Translational Toxicology and Therapeutics: Windows of Developmental Susceptibility in Reproduction and Cancer integrates toxicology and human health through coverage of environmental toxicants, genetic / epigenetic mechanisms, and carcinogenicity. The disciplines of toxicology and therapeutics are linked, relating toxicant exposure and genetic and epigenetic mechanisms to human health and development. The chapters explain specific cellular and molecular targets of known toxicants and offer a systematic approach to identify mutagenic, reproductive, and developmental toxicants. Coverage features discussion about cancer and mutation causes, toxicant exposures, gene-environment interactions, toxicant modes-of-action, and therapeutic strategies to reduce cancer risk. Readers can use this information to develop new animal models and tests to assess toxic impacts - specifically mutation and cancer - on human health.

Contenu

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 El…